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All posts by Native Earth
November 21, 2019 Native Earth
2019/2020 Season, Weesageechak
James Dallas Smith: A Magical Place That Shouldn’t Exist
November 4, 2019 Native Earth
“I want it to be born here…I want them to laugh, learn, and be amazed.”
A familiar face at Weesageechak, we’re delighted to have multidisciplinary Anishinaabe theatre artist James Dallas Smith return to the festival for the first time as a playwright. His first full script, Crossroads follows two Indigenous brothers who haven’t spoken in ages are trapped in a magical place that shouldn’t exist and forced to confront deities, their personal failings and their own complicated history. In this world, deities come in various different forms and lead the brothers through mysterious doors.
With history at its core in a fantastical world, this new theatre-musical promises to make you laugh. Crossroads will fill the evening of Friday November 22, alongside international artists Jasmin Sheppard (Sydney, Australia) and Dakota Camacho (Seattle, USA). You don’t want to miss it!
Learn more about James Dallas Smith
James Dallas Smith in Ipperwash (Native Earth). Photo by Kaytee Dalton
What inspired you to create the piece you’re bringing to Weesageechak 32?
I was lucky enough to be included in a piece called, Ipperwash that Falen Johnson and Jessica Carmichael co-created at the Blyth Festival. It’s a beautiful, heartbreaking story; the way Jessica cracked it open and presented it intrigued me. So it got me thinking about mine and as a middle aged man with a family if perhaps I was ready to tell a version of it. That same fall, I returned to Weesageechak for the first time in almost twenty years and was received by artists Monique Mojica, Gordon White, and Keith Barker in a way that felt like a homecoming. This encouraged me to start creating.
Why is Weesageechak the right place to present your work?
At its heart, this is an Indigenous story and this is a festival that has supported this sort of creation for more than 35 years. I want it to be born here.
What kind of reaction or effect do you want your piece to have to the audience?
I want them to laugh, learn and be amazed a time or two. I think humour is so important in telling our stories because they’re often challenging subjects to witness.
Where do you find your inspiration for your creative work?
Seeing, reading or hearing the stories of others – in books, plays, movies – often sparks something for me.
James Dallas Smith and Michaela Washburn in Almighty Voice and His Wife (Soulpepper). Photo by Dahlia Katz
Who is your Indigenous role model? How do they inspire you?
Currently, I have two: Keith Barker and Jani Lauzon. Beyond being incredible, gifted artists, I am in awe of the way they conduct themselves. They spread joy, remove fear, and just make everything they touch better.
What are you craving right now?
Pizza. Usually pizza.
What is coming up next for you?
I’m performing at Soulpepper in The Almighty Voice & His Wife by Daniel David Moses, which runs until November 10th.
< Artist Feature ListWeesageechak 32 Festival Line-Up >
artist featurew32
Natalie Sappier: Unveiling the Vocabulary of the Land
Following the successful run of her first play, Finding Wolastoq Voice, at the National Arts Centre, which was also in our 2017/18 season, Natalie Sappier-Samaqani Cocahq comes to Toronto to present her latest theatrical creation in development, MAW. Hailing from New Brunswick, this Wolstoqiyik artist shares a story inspired by her family, community and ancestral landscapes.
Aria Evans in Finding Wolastoq Voice. Photo by Andre Reinders
MAW is a two-spirited being who travels in different times, entering different bodies and minds to find answers and understanding of community history, upbringing and the magic of land connection. “I discovered that MAW carried an entity of more then one person and carried a spirit of many. It was more than telling a story of someone who had mixed blood.”
Following her development at the Animikiig Creators Unit, Natalie will bring MAW to Memorial Hall at the UNB Art Centre in December. But before that, catch the workshop performance on November 20th at Weesageechak Begins to Dance!
Learn more about Natalie Sappier
What inspired you to create the piece?
Writing my first play, Finding Wolastoq Voice, brought much healing into my life. I discovered a new way of sharing story. I began seeing stories in everyone and everything. I became fascinated with the magic of traveling into story with imagination and intention as I journeyed on my ancestral landscapes with Indigenous eyes and spirit. The lands hold many stories. The more I connect with it, the more I understand the importance of sharing them. MAW connects us to land, people and sky. With creating stories through MAW, it keeps my spirit open to what I feel needs to be heard and remembered.
I hope the audience will see the magic that lives in our environment and in ourselves.
On the land. In the water. Harvesting Medicine. Listening to my Wolastoqiyik Language. My Mother’s hair.
Natalie Sappier, Teachings along the River, 2013
Who is your role model and how do they inspire you?
My mother. She is my number 1 teacher. She is my number 1 storyteller. She is my number 1 healer. Many of my stories through songs, painting and writings are inspired by her. When I sit beside her I feel like I am on a canoe floating down a river so calm that you see the sky and the water becoming one. Her guidance keeps me grounded and her love gives me perseverance.
What’s the best piece of advice you’ve been given?
“Take care of yourself, it is your transportation.”
I am currently the Artist in Residence at the University of New Brunswick’s Arts Centre where I am focusing on creating my stories as well as I headlining the New Brunswick’s College Gala to raise funds for Indigenous Bursaries.
Ty Sloane: “Like all family reunions, it was a wild mess”
You may have caught a glimpse last year, and after another year of development at Animikiig Creators Unit, Ty Sloane presents his latest theatrical piece which has further bloomed and extended.
Nick Nahwegahbow and Yolanda Bonnell in Liminal (Hummingbird), Weesageechak 32. Photo by Kaytee Dalton
Hummingbird is a compelling story on discovering the truth and complexity of Indigenous identity sparked by a family reunion and the messiness that ensues. Inspired by Ty’s own experience, the story is told through the eyes of Ethan Par who returns to his birthplace of Winnipeg where he reunites with his mom, Sharon, from Edmonton to celebrate the wedding of his godmother, Asha. On his journey to find proof of his Indigenous identity, Ethan encounters a series of events. What starts as a weekend of celebration and searching, soon becomes a weekend of tension and unexpected endings.
Check out Ty Sloane’s Hummingbird on November 20th, alongside Jenn Forgie and Natalie Sappier!
Learn more about Ty Sloane
I was motivated by my friend Daniel Carter after I experienced a weekend in Winnipeg during 2017. My mom and I were going to my godmother’s wedding and at the time I’d recently been in contact with my womb-bearer. So, I decided I wanted to meet them, especially because I’d been on my journey to finding my status as a means of claiming my identity as an Indigenous person. Like all family reunions, it was a wild mess.
How did the piece change/evolve/develop from last year’s presentation at Weesageechak?
The first tipping point was when Yolanda Bonnell mentioned how I represented Indigenous women and also how complex the story was because it was actually mine. Since then, moving away from the source into one that would still touch on complexities of queerness, identity, families, intersectionality and also showing growth has been a challenge. I think the characters have grown more; they are more alive. My biggest challenge is making the protagonist show growth and separating myself from that journey.
Cole Alvis and Brendan Chandler in Liminal (Hummingbird), Weesageechak 32. Photo by Kaytee Dalton
There are so many stories right now about queerness and Indigeneity. But I haven’t seen much representation of a story like mine. I want to add to these ongoing stories to talk about mixed-race identity, the lateral violence I’ve faced from Indigenous folk, and the complexities of having a white, black, and Indigenous mother(-figure) in my life and how that’s shaped me as a person. I’d like the reaction to be one of questions and conversation.
Music like Nomvdslvnd, Jeremy Dutcher, Flume, and Khalid. Burlesque & Drag performers like Ravyn Wngz, Brad Puddin, Halal Bae, and Mx.Wolverine. Queer love stories. Theatre artists like Yolanda Bonnell, Saga Collectif, Raf Antonio, Jenn Forgie, Cole Alvis, and Kevin Matthew Wong.
A year ago I’d say someone like Leelee Davis, Naty Tremblay, and Kent Monkman. A few years ago I’d say Daniel MacIvor, Tanya Ryga, and William Esper. All my life maybe I’d say, my mom in different ways. Right now I feel the most teaching and the most inspiration from the water. That may be weird, but… I always find the most answers, the most peace, the most inspiration, the most therapy in a way from being at the water. People are too complex and human to be a role model anymore.
My mom said “People come into your life for a reason, a season, or a lifetime.” and when worrying about other people’s decisions to just say, “whatever” in letting go.
I’m craving Indigenous Queer Art Parties, Group Choreo in Burlesque, Theatre shows that have alarming and exciting levels of sex, intersectionality, and bodies similar to my core group, and follow-up action from people who choose to go to marches/strikes.
I’m part Chinese and have the immense pleasure of being part of the ‘Invisible Footprints’ series where I’m doing a photography project called ‘Fruit Basket’. It’ll be a project that highlights mixed-race East Asian and Southeast Asian folks. Too often I enter ethnic-specific spaces – like Indigenous ones – and have to erase parts of my mix in favor of the critical mass of Indigenous identity in a room. This series explores how mixed-race folk visibly show their ethnicity in their own way as an act of commentary on erasure.
I also want to continue Hummingbird. It’s a trans-national, intersectional story outside of what’s been offered to me, about identities and moms that need love and support.
Jenn Forgie: Disconnection and Un-Belonging
October 29, 2019 Native Earth
“This is a story I’ve wanted to share for many years, because I wanted to bring voice to the experience of disconnection and un-belonging, starting first with the Body.”
Seven Pieces is an interdisciplinary play that explores the effects of dissociation and the steps to healing one’s Self and Body, after childhood abuse and cultural erosion. Through dynamic and nuanced physicality, vocal expression and breath, Jenn Forgie tells the story of Kate and her child self Katie, guiding us through their childhood home, moments of denial of their Métis roots, the dull disconnect to their French Canadian culture, and the powerful force of religion as the shield between secrets, truth and what remains unseen.
Jenn Forgie and Lisa Nasson in Seven Pieces, Weesageechak 31. Photo by Kaytee Dalton
Developed as part of Native Earth’s Animikiig Creators Unit, Seven Pieces is a revealing tale of courage, healing, and reclamation of a woman who must face her past.
(Snippet from Seven Pieces)
CHILD KATIE: I’m an Indian?
MOTHER: We’re not Indian.
KATE: The je ne c’est quoi of shushed hushed languages
MOTHER/CHILD KATIE: Kilts and bagpipes and filthy Scots and—
KATE: The jagged lines of tight lips and severed bloodlines.
MOTHER: Before the long fade out buzz of the heat bugs in the maples
Since last festival’s short reading, the piece has bloomed further. Catch the extended version on November 20th!
Learn more about Jenn Forgie
I did not discover the “way in” to how I would tell it until I had a life changing experience with elephants in Thailand who were no longer free.
The story has evolved to a full, complete play; one character was revealed to be not their own character but to exist in the bodies of the two main characters. We have also been engaging in workshops, thanks to Canada Council for the Arts, exploring and developing the physical and vocal languages of the characters and integrating this with the script. I hope to continue to develop Seven Pieces this way through 2020. In addition, I am gaining clarity about the underlying theme around identity for the main character and I’ve been exploring the ways of weaving this into the script.
Cheri Maracle and Jenn Forgie in Seven Pieces, Weesageechak 31. Photo by Kaytee Dalton
I hope to offer a glimpse of the interdisciplinary aspects of the play; I hope they see the Light of this story and have a sense of the container it is built around. I hope they have a sense of the theme around Belonging and that they relate in some way, within themselves, to their own desires for belonging and experiences of un-belonging. I hope they want to see more of this play!
I find it in myself first, in my own lived experience, and respecting that and in coming from a place of truth and integrity. I am also inspired by the incredible artists I am privileged to work with.
This is a tricky question for me because I don’t have one mentor I am inspired by. I have several and they influence and inspire me in such varied and unique ways. I suppose in general I am very inspired by women who find their ways home to themselves, however and whatever that means. Their strength and courage inspires me every day and they are everywhere.
Of late, the best advice I’ve been given and I’m finally allowing myself to receive is that I don’t need to work so HARD! I can trust…I can relax into the work. As an actor in my own written piece, it is encouraging to hear “you don’t need to work so hard, Jenn. The writer has given everything you need right there in the text and breath.”
I am craving the resources, space and time to further expand the interdisciplinary elements and languages of Seven Pieces, with the artists I want to work with. I’m craving clarity about one character in particular, though I’m trying to relax and let her reveal herself to me when she’s ready.
I will be launching my website in the next few months, focused on my work as a writer. Primarily, I will be diving deeper into the next phases of writing and dramaturgy of Seven Pieces. And who knows what else is coming! I can’t wait to embrace it all!
Frances Koncan: Weirdly and Unnecessarily about Louis Riel
Photo of Erica Wilson, Frances Koncan, Erin Meagan Schwartz by Leah Borchert for 2018 Toronto Fringe
Winnipeg-based Anishinaabe playwright Frances Koncan combines humour with satire and history to deliver a poignant insight into the Canadian fur trade. As part of Animikiig Creators Unit, she has been working with mentors Jessica Carmichael and Lindsay Lachance for the past two years to develop Women of the Fur Trade, a story about the cultural inheritance of three 19th century women as they navigate the tumultuous world of the Fur Trade. “It’s also about the power of friendship and the tragedy of bad facial hair,” says Frances.
Women of the Fur Trade is an invitation to review what historical narratives we know of this land, and recognize the Indigenous and Métis heroes and leaders, all the women and two-spirited folks who were behind the image.
The play won first place at the 2018 Toronto Fringe New Play Contest, and second place at the Winnipeg Fringe New Play Contest. And in February 2020, it will premiere at the Royal Manitoba Theatre Centre as part of their season.
Catch the workshop performance of Women of the Fur Trade before its world premiere on November 21st!
Learn more about Frances Koncan
I was reading about Canadian history, especially the history of Treaty 1 territory and every story was told by men! Further, every story about the fur trade was somehow about Louis Riel, as if he was the only person who existed. I thought that was both hilarious and very annoying and wanted to write something else about it that was also as weirdly and unnecessarily about Louis Riel, yet not about him at all.
Last year the piece was a 60 minute work. Now it clocks in around 90 minutes. There are two new characters and a more linear and familiar narrative path through the story as opposed to how abstract it used to be. I think it’s sharper and smarter. I wrote the first draft in October 2017 and have changed a lot as a writer since then, which I think is evident in the script.
Anything but boredom. I never really set out with an expectation of what I want the audience to experience beyond simply a lack of boredom. Whether that’s anger, laughter, confusion, intense hatred…anything but boredom.
Deep inside my constant low-grade anxiety. I love generating weird ideas for absolutely no reason. Like fake Hallmark movie titles. Sometimes the ideas work and give me inspiration for a project!
Keanu Reeves. He’s a good, respectful person who works in a variety of genres. He doesn’t dismiss his less critically-acclaimed work. He doesn’t take himself too seriously. He’s a vampire who is going to live forever. I aspire to be all of that.
The play is premiering at the Royal Manitoba Theatre Centre. I kind of quit doing theatre and am working as a journalist at the Winnipeg Free Press right now. But I did get roped in to directing a production of Othello this winter. I also want to have a baby with a sperm-donor, on or before January 1st 2022. Mindy Kaling did it. Why not me?
Mark Dieter: Is money really the solution?
Hailing from Saskatchewan, the Saulteaux and Plains Cree actor and director, Mark Dieter, returns to Weesageechak for the second time as a playwright. Following RRAP, which was at Weesageechak in 2005, A Path of Ghosts and Warriors is a sequel which takes place on the same Canadian reserve.
The play is inspired by the current situation in Mark’s community, Peepeekisis First Nation, which is in its final stages of land claim negotiations with the federal court. “This play is a reflection of what I have seen and witnessed within my community in the last 30 years since we had first filed for our claim in 1986.” Exploring the effects of colliding interests, external influence and systemic change, we discover a community in the grip of reassessing its values.
Don’t miss the staged reading of Mark’s new play on Friday November 15th, alongside Zach Running Coyote and The Raven Collective representing Larry Guno.
Learn more about Mark Dieter
Native Earth has always been a great place to have new works developed and showcased for as long as I have known (since 1993). I have been privileged to participate in numerous festival events throughout the years as both a workshop participant and now as a playwright.
I am open to all forms of response, but I feel that laughter will be the one factor that connects everything; that laughter and the absurdities of life are important because they have been a part of our enduring legacy and our storytelling. I want the audience to look into their own communities and question whether the details of the plot are similar to their experiences. I want them to see their family, their brother, their sister, and all the people they know in their communities and ask themselves, “Is money really the solution?”
My community, no question.
My late father was a company man. He tried to provide a service and promote business on-reserve.
What is the best piece of advice you’ve been given?
“You’re going to meet a lot of people in this business. Always keep one foot on your base,” from Tantoo Cardinal, 1993. Epicure Cafe, Toronto.
The best development and support possible to make a better and marketable script for company submissions.
I have two other projects in development—Loaded which is an independent feature film, and an online web series titled, Kevin Stone. The latter project just had some recent movement with an interested company in Saskatoon who are looking to fund production.
Jasmin Sheppard: No straight and easy answer.
If you family was denied its culture by the impact of colonization, what then makes you Aboriginal?
As a Tagalak and Kurtjar Aboriginal woman with Irish, Chinese and Hungarian ancestry, Jasmin Sheppard‘s newest creation, The Complications of Lyrebirds, explores the impact of colonization and cultural suppression. Australia’s best-known native birds, lyrebirds have a superb ability to mimic the calls of other birds in order to appear more attractive. Using lyrebirds as a metaphor, Jasmin draws a parallel to the external pressures thrust upon Indigenous people to perform ‘blackness’, including adopting a certain way of talking and appearing. Her work speaks for people who are denied a voice and uncover an untold side of history.
Internationally acclaimed contemporary dancer and choreographer, Jasmin spent the last twelve years dancing for the renowned Australian company, Bangarra Dance Theatre, and earlier this year, completed a residency at the Campbelltown Arts Centre. Returning to Toronto after a riveting performance at Fall for Dance North Festival, we are delighted to have this award-winning artist at Weesageechak 32!
Photo by Pati Solomon Tyrell
Don’t miss The Complications of Lyrebirds on November 22nd, alongside Seattled-based multi-disciplinary artist Dakota Camacho!
Learn more about Jasmin Sheppard
As an artist who has spent the last 12 years with Australia’s premier Indigenous dance company, Bangarra Dance Theatre, I’ve been able to witness through the many people who have seen our work the expectation that is held on what makes a person a ‘true Aboriginal’.
With each of us coming from many different nations, backgrounds, family experience, it is clear that there is no straight and easy answer for us to provide white Australia. This work is a statement that says we don’t need to exemplify our Indigeneity.
Photo by Jeff Busby. Bangarra Dance Theatre.
I have had the opportunity to work and get to know many Indigenous Canadian artists, and I believe that our experiences share a great deal of likeness. My work will be supported and received with understanding by the community there in Toronto at Native Earth.
My work is still in its seed development stage, and to expose my creative process and a work in development will contribute to a stronger work by having its progress performed and shared.
For Indigenous audience: I hope to embed a sense of pride and self worth, despite personal histories or inter-generational trauma. For non-Indigenous audiences, I hope to shed some light on the historical experiences of First Nations Australians and create some understanding for the pressures that a lot of Indigenous people feel.
In my cultural heritage. In the everyday simplicity that strikes me. In my body.
My grandmother, Ivy, who has experienced an enormous amount of hardships and trauma, but whose beautiful, soft spirit has never bent to the harsh reality of being a fair skinned Aboriginal woman in Queensland.
Don’t rely on motivation, it is fickle! Build self determination.
Mangoes and Summer.
Zach Running Coyote: Hum my songs the whole bus ride home
“In theatre, a triple-threat performer is one who can act, sing and dance…He can act, sing and dance, but he’s also an accomplished composer, lyricist, playwright and a born storyteller.” – Calgary Herald
Calgary-based Nehiyaw artist, Zach Running Coyote comes to Weesageechak for the first time with his debut work as a playwright. Kohkum & me is a virtuosic folk musical about an adopted young Indigenous man who is headed to Vancouver on a Greyhound bus in search of his birth mother. A whirlwind journey filled with biting humour and powerful songs, we discover ancestors using payphones, David Bowie as an Ice Monster and Jesus as an Indigenous Grandmother.
Kohkum & me was inspired by Zach’s own endless bus trips and the numerous people he met, including an elder who survived the residential schools and has learned to heal herself. Featuring Zach himself, the play premiered at Calgary’s Motel Theatre in August as part of his graduating project at Rosebud School of the Arts. We’re excited to see Zach take this piece to the next step at Weesageechak!
Learn more about Zach Running Coyote
“I have been stripped of knowing where I come from. Lies are written in the pages of a colonizer’s ledger that threaten to determine my place. But it is my ancestor’s blood, not a white man’s ink that runs in my veins.”
Growing up in a Christian home with no connection to who I am, Kohkum & me is my autobiographical myth of how I learned to look into a mirror and recognize a child of Creator.
I did a project on Native Earth Performing Arts in my theatre history class, and I’ve been pretty obsessed ever since. Many of the artists I admire the most have developed work through Weesageechak, and it’s so very fulfilling to do the same!
I hope my truth is met with listening, open hands. I hope that you learn something about yourself. I want you to hum my songs the whole bus ride home. I want to inspire the child and elder within each person, and invite the audience into a healing circle where we all, in the words of the show’s final song, “Listen to the Old Ones breathe.”
The hidden elders living on the streets. They are the glowing embers of a sacred fire.
Who is your role model? How do they inspire you?
Buffy Sainte Marie who said, “Take a chance on the spirit of the wind.”
To eat before going to bed. Keeps the nightmares away.
A trip to some hot springs.
The Napi Project with Making Treaty 7 and Lunchbox Theatre, as playwright and performer.
Ed Bourgeois: Honouring those who continue to whisper in our ears
“In a world with increasing ties through technology, many of us remain painfully disconnected — from our homelands, our predecessors and the touchstones that ground us in a shared reality.”
Oregon-based playwright Ed Bourgeois comes to Weesageechak 32 with his latest creation, River of Blood. Set in the early 18th century, Joseph, a modern Indigenous man, confronts the true nature of his mixed ancestral heritage through his relationship with his daughter.
We don’t always recognize or know how to relate to the trauma, the memories, the dreams and the voices that reach out to us from the past. River of Blood honours the ancestors — those who wished us love, those who sent us messages, and those who continue to whisper in our ears.
Catch the staged reading of Ed’s play on November 14th, alongside Christopher Mejaki, Cole Forrest and Maria Campbell, Yvette Nolan, Marilyn Poitras and Cheryl Troupe.
Learn more about Ed Bourgeois
The specific historical setting of River of Blood — New England, New France and Iroquoia in the early 18th century — represents an interweaving of cultures that is barely mentioned in US textbooks today, despite that fact that so many of us have all three roots in our family trees. The complexity and subtlety of multilingualism and diplomacy are far removed for US audiences, but I expect them to play better with Canadian audiences, whose ears are more attuned to the many shades between black and white.
I hope the audience will see themselves in the mixed people on stage, and have an understanding that those people are dealing with gifts over which they do not have control. We are made up of all the things that have flowed downriver to us.
To be inspired is to be in spirit. The work comes from listening carefully to the spirit world and then not getting in the way with our egos.
Oglala Lakota visual artist Walt Pourier. “To be inspired is to be in spirit” is his quote. Walt reminds me to work from our values.
“Stop acting and just do it!”
Quiet time to get the next three plays in my brain down on paper.
Coordinating the pilot Native Artist Residencies + NPN Creation Fund project: The Indigenous Road Show, devised with Indigenous artists and director in residence at Bunnell Street Arts Center in Homer, Alaska. The work will premiere in Portland, Oregon next summer.
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Title: Pauri Garhwal
Subject: Timli Sanskrit Pathshala, Garhwali people, Govind Ballabh Pant Engineering College, Hemvati Nandan Bahuguna, 1999 Chamoli earthquake
Collection: Uttarakhand District Templates
Cities and towns in Pauri Garhwal
Dogadda
Kashirampur
in other districts
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Uttarakhand district templates
Pauri Garhwal district
Uttarakhand, Chamoli district, Dehradun district, Almora district, Nainital district
Uttarakhand, India, Pauri Garhwal district, Rhododendron, States and territories of India
Uttarakhand, India, Pauri Garhwal District, Pauri, States and territories of India
Timli Sanskrit Pathshala
Sanskrit, Information technology, Uttarakhand, India, Tantra
Garhwali people
Uttarakhand, Delhi, Garhwal division, Himachal Pradesh, Punjab, India
Govind Ballabh Pant Engineering College
Uttarakhand, India, Uttarakhand Technical University, Principal (university), Undergraduate education
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By Javeed Ali
Javeedaliofkashmir@gmail.com
International Quds Day is an important day for humanity. It is the day to express our solidarity with the oppressed people and demonstrate the resentment against the oppressors. It is the day which breaks the back of Zionist forces and their allies. It is the day of persecuted ones against the tyrants. It’s a day of remembering Quds (Jerusalem), the entire Palestine, and the catastrophe and calamity that was brought upon them with the creation of the State of Israel.
Quds Day was founded by the revolutionary leader of Islamic Republic of Iran late Imam Khomeini (R.A.) and laid the solid foundation for the freedom struggle of Palestine which is illegally occupied by Israel. It is commemorated every year on the last Friday (Jumut-ul-Vida) of the holy month of Ramzan and is also designated as Youmi Quds. Quds Day was initiated by Imam Khomein (R.A.) in 1979 after he established Islamic system in Iran.
The Israeli forces are killing, bombarding and torturing the innocent Palestinian people in a planned manner. Palestinians are struggling against the forced and illegal foreign occupations since last 6 to 7 decades and Israel is using every possible oppressive method to suppress the voice of helpless people.
The first Qiblah Muslims prayed towards is Al-Aqsa mosque or “Bait-ul-Muqqadas” (Holy place) which is now in Jerusalem (Quds). Most of the prophets of Allah were appointed in this city. This is one of the most blessed places in the world and was the first Qiblah (direction) of Islam. Prophet Mohammad (SAWW) with Ahlulbayt (A.S.) and companions used to say their prayers facing towards its direction. Prophet Mohammad (SAWW) offered his prayers facing Bait-ul-Muqqadas for thirteen years when he was in Mecca then for seventeen months after emigration to Medina. The foundation for Bait-ul-Muqqadas has been laid by Prophets of Allah Almighty and they used to spend their sacred life there besides offered their prayers there also. Prophet Mohammad (SAWW) has said that Masjid-ul-Haram in Mecca is the first mosque that was constructed in the world and then Bait-ul-Muqqadas was the second mosque which was build 40 years later after the establishment of Masjid-ul-Haram. According to the Holy Quran and Islamic traditions, Al-Aqsa Mosque is the place from which Prophet Mohammad (SAWW) went on a spiritual night journey (Shabi Meraj) during which he rode on Buraq, who took him from Mecca to al-Aqsa. Prophet Mohammad (SAWW) tethered Buraq to the Western Wall and prayed at al-Aqsa Mosque and after he finished his prayers, the Angel Jibril (A.S.) traveled with him to heaven, where he met several other prophets and led them in prayer. There are traditions regarding Bait-ul-Muqqadas 1. Whosoever visits Bait-ul-Muqqadas with lot of zeal and religious fervour then he or she will enter the heaven. 2. If anyone will offer two Rakats of prayers in Bait-ul-Muqqadas then his sins will be pardoned, his heart will always stay attached to Allah Almighty and he will keep reciting the eulogy of Allah Almighty. 3. Whosoever gives alms to destitute people in Bait-ul-Muqqadas will save himself from the fire of hell. It is well established fact that Quds is an important part of Islam and its liberation from the Zionist Israel is paramount for Islam. Therefore, whole Muslim Ummah leaving apart their sectarian differences should unite under one umbrella and fight for the Palestine freedom struggle with greater energy. Quds Day is a unique opportunity for us to unite under one platform and we should provide all the resources available to us for the just cause of Palestine.
Quds Day is not only aimed for Palestine but it is also meant for all the oppressed nations. It is the day to oppose all the oppressors including the notorious oppressors America, Israel and their allies. It is the day to reenergize ourselves to fight against the falsehood. It is the day which demarcates between the right and wrong. The righteous ones do support Quds Day rallies whole heartedly but the hypocrites oppose it by tooth and nail as they prove their friendly relations with America, Isreal and other Zionist forces. They don’t permit Quds Day demonstrations and always create hurdles and try to sabotage it. At times, they attack it through their paid mercenaries like they did in Quetta, Pakistan on 3rd September, 2010 when 60 participants of Quds Day rally were martyred in a suicide attack by terrorists. Moreover, the Nigerian Army who are subservient to the Zionists and to prove their loyalty to masters, perpetrated a bloodbath of peaceful participants in the Quds Day rally at Zaria, Nigeria on 24th July, 2014 which claimed the lives of 33 peaceful pro-Palestinian protesters including the three sons of the leader of Islamic Movement in Nigeria Sheikh Ibrahim Zakzaky. So it is crystal clear now that the Israel along with its master America and their collaborators are the biggest enemies of Islam and anything which goes against their stand, they thwart it with all their available resources. It is very unfortunate for the Muslim World that some Arab countries are hand in glove with the America and Israel to persecute Muslims all over the world. Recently Donald Trump, the President of US was conferred accolades in the holy land of Hijaz despite the fact that the US policies are always formulated against Islam particularly against the oppressed people of Palestine.
Supreme leader of Islamic Republic of Iran Ayatollah Syed Ali Khamanai has predicted in 2015 that “God willing, Israel will cease to exist in next 25 years”. He further said that America is Grand Satan (Shaitan-i-Buzurg) which is evil to humanity and Islam. He further reiterated to chant slogans like “Marg Bar America”, “Marg Bar Israel” (Down with America, Down with Israel) on Quds Day and it should reverberate the atmosphere throughout the world. He stated that these slogans are not against the people of the respective countries but against the policy of the concerned authorities. Israel along with its masters America with full backing and support from Pro-Zionist Arab countries started crises in Iraq and Syria through the the ISIS (Daesh) terrorists to trammel the freedom struggle of Palestine. The Resistance Movement of Lebanon Hezbollah who had earlier defeated Israel in 2006 had made a blueprint to liberate Quds and Palestine from the clutches of Israel but it was impeded by Israel and its associates who orchestrated a civil war in Syria and turmoil in Iraq.
23rd June, 2017 (Jumut-ul-Vida) is the day of remembering Quds (Jerusalem), the entire Palestine, and all the oppressed people of world including Kashmir, Yemen, Bahrain, Burma, Nigeria, Afghanistan, Pakistan, Nigeria and so on. All the Islamic Scholars and Imams of the Masjids should highlight the issue of Masjid Al-Aqsa which is under the illegal and forced occupation of Jewish forces in their Jumma-tul-vida sermons and organize special prayers for the liberation of Palestine from Israel. After Friday prayers, peaceful demonstrations should be held all around the globe to press upon international community to liberate Palestine from the illegal occupation and give befitting reply to Israel that Palestine is not alone. Everyone with with heart should participate in these rallies as it the religious obligation to confront the oppressor and stand with the oppressed people.
I want to conclude with the slogan, “From the River to the Sea, Palestine will be Free”.
Posted in OpinionTagged Javeed Ali, Quds Day
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Peerzada Sirajudin Makhdoomi wishes happy Eid to Muslim Ummah
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A Kid Like Jake Matinee
14:00PM $28/$23
dream of passion productions presents: A Kid Like Jake
For Tickets Click Here! Ticket prices (including all taxes and fees):
Early Bird Pricing (before April 1): $23
Regular: $28
Student/Senior/Equity/Industry: $23 Preview (April 22): $18 advance / Pay What You Can at the door
2 for 1 relaxed performance: April 28
On the eve of the admissions cycle for Manhattan’s most exclusive private schools, Alex and Greg have high hopes for their son Jake, a precocious four-year-old who happens to prefer Cinderella to G.I. Joe. But as the process continues, Jake’s behaviour becomes erratic and perplexing, and other adults in his life start to wonder whether his fondness for dress-up might be cause for concern. The story of a husband and wife struggling to do right by their son, A Kid Like Jake is a study of intimacy and parenthood and the fantasies that accompany both.
Warnings: Coarse language
Cast and Team:
Director: Fay Nass
Actors: Stefania Indelicato, Brent Hirose, Beverly Elliott, Lindsay Nelson
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interviews, rachel dukes, rbm, spx spotlight |
SPX Spotlight 2017: An Interview with Rachel Dukes
It's another entry in Panel Patter's not Patented SPX Spotlight feature! We're ready to provide you with some great pre-show coverage for one of the best comic shows in the United States! In a show with nearly 700 exhibitors, we'll help you find some of the best! You can read all our SPX Spotlights from 2017 and prior shows here.
We at Panel Patter love Rachel Dukes, the prolific anthology contributor and creator of Frankie Comics. Rachel's style works great for telling the story of Frankie, her stray cat, with its ability to capture emotion in a few lines. At the same time, she can use that same emotion to explain the dangers of the American health system or a loving couple tied to a space program that's using them both. She's graciously agreed to many an interview over the past few years, and I had a chance to ask her a few questions in advance of the Small Press Expo about re-starting Frankie Comics, her varying comics projects, and why politics and comics are so intricately linked.
Rachel Dukes and Fankie, in her own lines.
Rob McMonigal: Though you're very busy contributing to various comic anthologies and outlets (more on that in a moment), the biggest thing you're known for is cats; specifically Frankie Comics, the adventures of your own feline. How did Frankie Comics get its start?
Rachel Dukes: Frankie showed up with a pack of strays outside my partner’s and my first apartment back in 2009. While the other strays were mostly feral and scattered within a few days, Frankie stayed around the apartment complex, going door-to-door looking for food and attention. She started sleeping overnight with us pretty quickly before we decided to keep her inside full time. She made her comic debut way back in journal comics I was creating at the time.
Frankie Comics, as it’s own series, began in 2013 when I was in grad school at The Center for Cartoon Studies in Vermont. My partner had moved back to California for work during my second year, so I spent most of my time alone in my apartment with Frankie working on my thesis; so it was only natural for me to draw comics about our hijinks together. I was posting my work on Tumblr and the very first strip Frankie strip I posted (Life with/out a Cat) went viral almost immediately (after it was shared on 9Gag without attribution). Some of the people who read the strip found their way back to my Tumblr and I’ve had a small loyal fanbase for Frankie ever since.
A Sample Frankie Strip
Rob: Lots of comic folks write stories about their cats. What do you do to make Frankie stand out from the crowd?
Rachel: Most classic cat comics focus on cats being aloof, sarcastic jerks who enjoy destroying furniture. (And, yes, of course they can be!) But Frankie isn’t really like that by and large - she’s very lovey and involved in what I’m doing throughout the day - so the series is almost a flip of the traditional cat comic; it’s about companionship, teamwork, sweetness, and the inquisitive nature which causes the inevitable destruction of personal belongings.
Rob: I've seen your name show up in so many different places of late, including The Nib (one of my favorite sites), Taneka and Sfe's Beyond, the Bottom's Up anthology from Birdcage Bottom Books (available at SPX) to working with one of comics' great indie publishers, Spike Trotman (Tim'rous Beastie). How do you stay so active in the anthology scene? How do you approach such varied projects?
Rachel: I find anthologies can be a wealth of opportunity in a creative sense. They’re a good way for cartoonists to gain visibility and practice working (either writing or drawing) in genres that they might not consider within their wheelhouse. They’re also a great excuse to collaborate on comics if that’s not something you do normally. Comic anthologies were my first foray into being published during my teen years, so they’re something I’m sort-of-unintentionally always on the look out for; just because they’re part of my early-comics DNA.
My regular involvement in anthologies now is a combination of attentiveness and luck. I follow thousands of cartoonists, publishers, and zinesters across social media so I see a good cross-section of new projects being announced. I pitch for things when I have ideas, and I ask around if I like a genre but don’t have an idea of my own. For instance, with Beyond, I wasn’t well-versed in sci-fi (aside from X-Files) and was afraid to write something to pitch. I asked around looking for writers and got lucky: Nicasio Silang also wanted to submit but needed an artist. And we were lucky again in that our pitch was accepted!
(If you don’t want to worry about following all the cartoonists and publishers you know simply to keep an eye out for anthology announcements, I’d recommend following Comic Ops on Tumblr. Sarah W. Searle posts anthology and freelance opportunities there fairly regularly.)
For anthology work I do my best to approach each story with it’s own needs in mind first. What is the story about? What art style serves that best? Then follow-up with “what do the writer and I personally find engaging about this and how much of that can play up throughout these pages?”
Rob: What can people pick up from you at SPX this year?
Rachel: I'll have plush Frankie dolls, shirts, posters, original art, and a SPX-exclusive 80-page Frankie Comics collection of issues 1-4 (provided they arrive from the printer on time). I'll also have limited quantities of the Oath (queer superhero) anthology by Mary's Monster, the Bottom's Up anthology by Birdcage Bottom Books, Care Bears: Puzzling Path by Roar Comics, and Not So Secret Society: Tale of the Gummy by KaBOOM.
The adorable Frankie Plush
Rob: What's coming up for you after SPX in terms of conventions or creative projects?
Rachel: My big project for the next six months is completing a 120-page Frankie Comics collection. I’m currently drawing Frankie Comics #5, which will start updating online at frankiecomics.com and Go Comics (every other week) starting in mid-October. While those are running, I’m going to redraw Frankie Comics issue #1, update the artwork for all five issues, and recolouring the series so that it’s in glorious full-colour. (I’ll likely also end up drawing comics that will be exclusive to the book.) After a few years of prioritizing freelance over Frankie, I’m pretty excited to put this all together. I’m posting the new Frankie Comics strips online early for Patreon subscribers, and it’s been a treat to be able to interact with readers again (and share cat pics!) after the long gap between issues. (Issue #4 came out in April 2017.)
SPX is my last confirmed convention for 2017. Frankie Comics #1-4 (the mini-comics) and many of the anthologies I’ve contributed to are out of print, which gives me an opportunity to take a break from conventions and use that time to make new comics. I had several projects I had to back-burner for the past two years while I completed previous obligations and acclimated to living with a chronic autoimmune disorder. I have a series of comics business tips, tutorials, and resources I’ve been wanting to launch as a book and website that I’m looking forward to finally dedicating some time to; alongside smaller personal comic essays on gender and women’s healthcare in the US.
In a similar vein, there’s a local (Los Angeles) true-crime story from September 2000 that has been weighing on me for a few years: a man was killed because California laws (surrounding hospitalization and mental health care) impeded police from assisting a woman who repeatedly asked for their help in the weeks leading up to a psychotic break. Seeing the rise (in publication) of incidents where police mishandle calls reporting mental-health disturbances, it feels relevant to reexamine the 17-year-old case and see if we’ve made any real progress since then.
I know the latter is a significant shift away from silly sweet cat comics. While I’ll never quit cat comics all-together --they take up too much space in my brain and my heart-- I’m greatly looking forward to peppering other new genres in there come 2018. I hope readers will stick with me for whatever the next adventure brings.
Rob: Lots of people involved in comics are active politically, especially on the Left. How can comics help the causes we care about in America's current political climate?
Rachel: There’s been an ongoing discussion about representation in comics over the last few years; how representation of different cultures, ethnicities, and marginalized groups benefits readers and creators (both from inside and outside those communities)... It’s important stuff and I feel like I have friends that are better educated to speak on it (look up work by cartoonists Mady G. and Ben Passmore) but I’ll touch on my own experience for a sec because you asked.
I was brought up in a very sheltered way, urged to blend in for my own protection. When my family found out I was queer: my mother made a point that, while I was free to build a life with whomever I wanted, she felt that it was in my best interested to not be “loud” about it -- that my life would much harder if being queer was a visible part of my personal branding; she worried that people would find me offputting if I continued to yell about LGBT+ issues, etc. And I mulled over that for a long time into my mid-twenties, trying to find a balance between being honest with people and being polite... and I learned a lesson in how silence only aids ignorance and misunderstanding.
If you’re a white able-bodied person hanging out with primarily white able-bodied people, you’re not going to be intimately aware of the issues that people of colour face, or what people living with disabilities or invisible illness face. It’s easy to make false equivalencies when you’re truly unaware of what other people are going through. You’re not going to know about ADA laws until you’re with someone who needs them. You’re not going to know the legal and social hurdles of gender transition until someone you know goes through it, until someone says something, or until you’re introduced to media that covers those topics.
My family was completely unaware about trans issues until Caitlyn Jenner. Despite Jenner being a far-less-than typical representation of the community she opened the door for my family to have some Trans 101 conversations. We started talking about gender as a social construct, my grandfather saved me the National Geographic issue that was about gender identity, that sort of thing... Hamilton allowed us to have conversations about immigration and government. My younger sister learned all about the Holocaust from Netflix and Maus because she somehow missed that history lesson between her two elementary and middle schools... Media is the opportunity to bridge gaps of interpersonal and historical understanding, to create exposure for people and causes that we may not be aware of otherwise. Comics are a part of that. Great recent examples include March by John Lewis, Andrew Aydin and Nate Powell; The Best We Could Do by Thi Bui; and Comics for Choice edited by Hazel Newlevant, Whit Taylor and Ø.K. Fox.
Visibility - being visible and creating media that help people and causes become more visible - can only lead to greater awareness and help us understand each other better, help each other better, and to grow as individuals, a nation, and as human gosh-dang beings. So we have an opportunity as creators to help lift each other up by promoting and creating comics and media that can help bridge those gaps and make change.
Rob: That's a really thoughtful answer. Thanks for taking the time to do this, Rachel! Hope to see you at another show soon.
Rachel Dukes will be at the Small Press Expo, but if you can't make it, her website is here.
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This page shows the latest Zinfandel news and features for those working in and with pharma, biotech and healthcare.
Another Alzheimer's bust as Merck & Co stops verubecestat study
Since the start of the year, Boehringer Ingelheim has stopped development of its PDE9a inhibitor BI 4093906, Takeda and Zinfandel abandoned efforts to repurpose diabetes drug pioglitazone for the disease, and
Takeda and Zinfandel abandon Alzheimer’s drug
Pioglitazone failed to show therapeutic improvements in late-stage testing. A phase III trial of pioglitazone in Alzheimer’s disease has been terminated by Takeda and partner Zinfandel Therapeutics after it ... Takeda joined forces with Zinfandel on
Takeda continues Actos resurrection as Alzheimer's drug
Late-stage trial will see if pioglitazone can delay disease progression. Takeda and partner Zinfandel Pharma have started a phase III trial of pioglitazone in people at risk of developing the ... Earlier studies of pioglitazone in symptomatic AD patients
Non-amyloid therapies emerging for Alzheimer's at AAIC
Takeda and Zinfandel Pharmaceuticals highlighted a new approach to identifying individuals who are at risk of developing Alzheimer's dementia which could be used to support clinical trials of early treatments.
Creative partnerships
Preclinical. 100. Zinfandel Pharma/Takeda. TOMM40 assay, biomarker for risk of developing Alzheimer's disease.
Takeda signs Alzheimer's deal for Actos
Under the partnership deal, Takeda has licensed the rights to an assay from the small US company Zinfandel Pharmaceuticals that it plans to use to identify high-risk older adults who ... The biomarker is being developed by Zinfandel to identify healthy
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Brexit: All you need to know about the UK leaving the EU
As the UK officially notifies the European Union that it is leaving, here is an easy-to-understand guide to Brexit - beginning with the basics. What does Brexit mean? It is a word that has become used as a shorthand way of saying the UK leaving the EU - merging the words Britain and exit to get Brexit, in a same way as a possible Greek exit from the euro was dubbed Grexit in the past. Why is Britain leaving the European Union? A referendum - a vote in which everyone (or nearly everyone) of voting age can take part - was held on Thursday 23 June, 2016, to decide whether the UK should leave or remain in the European Union. Leave won by 51.9% to 48.1%. Find the result in your area What was the breakdown across the UK? England voted for Brexit, by 53.4% to 46.6%. What changed in government after the referendum? Image copyright PA Britain got a new Prime Minister - Theresa May. How has the new PM done so far? What about the economy, so far? What is the European Union? What is Article 50? Yes. Yes.
http://www.bbc.com/news/uk-politics-32810887
Related: International Retailing • MUNers' talk • antoinerenault • Brexit • Visual Merchandising Research
Businesses will crumble under strain of minimum wage hikes, warns CBI chief "Everybody wants to see higher wages at the bottom end of the labour market. And that's a laudible objective that business will get behind," he said. "But Government pushing that rather fast is a gamble, and it's not obvious that businesses will be able to cope with that level of imposed wage cost increases without a reduction in working hours." Mr Cridland said smaller high street firms, which are already dealing with the triple burden of high rents, falling prices and fewer shoppers would find it particularly hard to adjust. Iain Duncan Smith, Work and Pensions Secretary, celebrates the announcement
Big Tech Stocks Affected Due to Trump Immigration Ban Trump Immigration Ban Donald Trump has not had an easy time of it trying to enforce what was intended to be his landmark national security executive order. The Trump immigration ban was halted for the second time, now by U.S. What is Brexit? - dummies By Ashley Watters, Abshier House Brexit is the term used to refer to the United Kingdom’s decision to leave the European Union (EU) and is a shortened version of British Exit. On June 23, 2016, the UK decided to officially sever ties with the EU. This monumental decision came as the result of a referendum—or public vote of nearly all citizens of voting age—in which more than 30 million people voted. Brexit background The European Union is a group of 28 European countries that are tied by an economic and political alliance.
Why Vote Leave - Vote Leave We will be able to save £350 million a week We can spend our money on our priorities like the NHS, schools, and housing. We'll be in charge of our own borders In a world with so many new threats, it's safer to control our own borders and decide for ourselves who can come into this country, not be overrules by EU judges.
Brexit: No substantive talks for 12 months, Herman Van Rompuy predicts Image copyright AFP/Getty Images Substantive Brexit talks between the UK and the rest of the EU are unlikely to start much before the end of 2017, a former European Council president says. Speaking to the BBC, Herman Van Rompuy said negotiations were unlikely until a new German government was formed after next September's election. The talks will be tough but hopefully of mutual benefit, he said, adding the UK had to make the "first move". He described the UK's decision to leave the EU as a "political amputation".
The environmental concerns of shoppers The environmental debate often focuses on climate change, driven over recent years by high profile events such as the Copenhagen and Cancun summits. Climate change opinions Despite the ongoing debate about climate change, shoppers’ opinions hardly changed between 2009 and 2011, as these findings from IGD's report, Environmental Sustainability - How to Engage Shoppers, shows: Brexit is a disaster for British fashion Hadley, you’ve written on Brexit elsewhere in the paper, but not in your style column. Why is that? Robert, by email You’re right, Robert! I have stayed away from Brexit in this column because that would mean looking at what it means for the fashion industry, and the answer to that is, well, no one knows.
EU referendum: Nigel Farage backtracks on Vote Leave's '£350m for the NHS' pledge hours after result Nigel Farage has disowned a pledge to spend £350 million of European Union cash on the NHS after Brexit. The Ukip leader was asked on ITV’s Good Morning Britain programme whether he would guarantee that the money pledged for the health service during the campaign would now be spent on it. Speaking on the morning of the referendum result he however said he had never made any such pledge. Lib Dem conference and Labour leadership Summary Nick Clegg makes his first speech to a Lib Dem conference as EU spokesmanFormer deputy PM says leaving the EU's single market would do "untold damage"Jeremy Corbyn says he will "reach out" to MPs if he is re-elected Labour leaderTheresa May is to criticise the West's response to the migration crisis at a UN summit None
UK Retail after Brexit - Centre for Retail Research, Nottingham UK UK Retail after Brexit What Will Happen? (13 July 2016) Multinational corporation - Wikipedia A multinational corporation or worldwide enterprise[1] is a corporate organization that owns or controls production of goods or services in one or more countries other than their home country.[2] It can also be referred to as an international corporation, a transnational corporation, or a stateless corporation.[3] There are subtle but real differences between these three labels, as well as those labels of multinational corporation and a worldwide enterprise. Overview[edit] Toyota is one of the world's largest multinational corporations with their headquarters in Toyota City, Japan. A multinational corporation (MNC) is usually a large corporation incorporated in one country which produces or sells goods or services in various countries.[4] The two main characteristics of MNCs are their large size and the fact that their worldwide activities are centrally controlled by the parent companies.[5] MNCs may gain from their global presence in a variety of ways.
Made in Ethiopia: Fashion's Next Sourcing Hub? ADDIS ABABA, Ethiopia — All is not what it seems in the Ethiopian capital. Had you failed to notice the small huddle of men wearing hard hats discussing ‘lean manufacturing,’ you might have mistaken last month’s shoe factory tour for a religious festival. Dressed in their finest Abyssinian gowns, a group of Ethiopian women greeted guests with rose petals as frankincense wafted through the air inside a building of immense proportions. Surrounded by local dignitaries in sharp suits watching the hostess perform an elegant coffee ritual, the delegation of casually-dressed Americans looked understandably self-conscious. “Gosh,” one murmured to another, as he was given a slice of ceremonial himbasha bread.
Nigel Farage says Leave win marks UK 'independence day' Nigel Farage has claimed victory in the EU referendum for the Leave campaign, saying 23 June would "go down in our history as our independence day". The UKIP leader told supporters at a Brexit party: "Dare to dream that the dawn is breaking on an independent United Kingdom." With 335 out of 382 results declared, the BBC has forecast a Leave win. The English shires and Wales voted for Brexit while London, Scotland and Northern Ireland backed a Remain vote.
Related: Dissertation Topic - sahrabouras - Brexit - General Economics - Brexit - International Retailing - MUNers' talk - antoinerenault - Brexit - Visual Merchandising Research - Girl Talk - Merchandising & Packaging Shops - Small Talk Resources - Teacher Talk Time - Interactive visual merchandising - Health Talk - Talk - WHISTLES - Buying & Merchandising - buying and merchandising - Plain Talk - Grit (real talk) - Visual Merchandising research - Poppy Talk - F/T - paper cd case - La Stickerie - Capitalism Is The Crisis (Full Movie) - YouTube - Who Runs the World ? - Network Analysis Reveals 'Super Entity' of Global Corporate Control | PlanetSave - 1107.5728v2.pdf - Fair Labor Association - Education is Ignorance, by Noam Chomsky (Excerpted from Class Warfare) - Forbes Welcome - Poppytalk - Occupy Wall St - The Revolution Is Love - YouTube - Presidential Libraries and Museums of the National Archives - Motivation - YouTube - HUD/U.S. - The High Price of Materialism - YouTube - Finally, A Rich American Destroys The Fiction That Rich People Create The Jobs - Business Insider - The Overjustification Effect « You Are Not So Smart - Heterodox economics: Marginal revolutionaries | The Economist - Government debt - Demonocracy.info - Economic Infographics
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Phil on Film Index
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Review - Elite Squad (Tropa de Elite)
"God help you if you use voice-over in your work, my friends. God help you. That's flaccid, sloppy writing. Any idiot can write a voice-over narration to explain the thoughts of a character"
– Adaptation (2002)
While the above line – spoken by Brian Cox as Robert McKee – overstates the case somewhat, it's easy to sympathise with McKee's sentiment when faced with a film like Elite Squad. Voiceover narration can be a potent tool in a filmmaker's arsenal, but it's one that must be handled with kid gloves. For every perfectly pitched film like Days of Heaven, Goodfellas or The Assassination of Jesse James by the Coward Robert Ford, there are dozens of films in which the soundtrack chatter feels like a lazy shortcut; more of a distraction than a guide. In Elite Squad, the central character is a Brazilian police captain named Nascimento (Wagner Moura), who commands the marine-like BOPE squad, a highly trained elite unit that's unafraid to go where regular officers fear to tread. Set in Rio in 1997, the film follows Nascimento as he searches for a young replacement to take the reins after his impending retirement, and every step of this journey is narrated by the character in the same droning, emotionless tone. Nascimento's ceaseless commentary explains in detail his character's thoughts, feelings and actions, and then – as if that wasn't bad enough – the seemingly omniscient narrator offers the same service in scenes that have nothing to do with his character, dutifully spelling out the stories of young cadets Neto (Caio Junqueira) and Matias (André Ramiro).
The way director José Padilha leans on Nascimento's non-stop narration suggests he lacks confidence in his own ability to tell this story. This is a shame, because he showed in his previous feature – the outstanding Bus 174 – that he is capable of handling narrative with a lighter, more intuitive touch. He tries to maintain some semblance of documentary-style rigour in this would-be exposé of Brazilian law enforcement, employing a gritty, unvarnished aesthetic, but while Elite Squad's authenticity is never in doubt (former BOPE captain Rodrigo Pimentel helped bring his own book to the screen) its value as a piece of cinema is harder to determine. After opening with an onslaught of loud music and aggressive, heavily edited camerawork, the picture quickly goes limp. For all of the brutality on display the action is repetitive and lacking in real impact, and as Padilha develops his separate story strands involving Nascimento, Neto and Matias, he doesn't give us enough time with any of them to really get a sense of them as people. Most of the time Elite Squad just feels like an inferior version of TV's The Shield, sorely lacking that show's strong characterisations and its ability to skilfully interweave its disparate story elements.
About an hour into Elite Squad, Padilha finally begins to give his movie a sense of shape. The so-so storyline of the opening half – the desire to clean up Rio's streets ahead of the Pope's visit – is unceremoniously dropped, and the director finally focuses on more personal dramas. The boot camp sequence, in which Nascimento puts a group of wannabe cadets through a punishing regime, is the first really engaging section of the film, and the subsequent revenge mission Nascimento launches against local kingpin Baiano (a snarling Fábio Lago) is reasonably compelling. Aside from this efficiently staged action, Elite Squad does have some interesting points to make. It presents the Brazilian police force as being as corrupt and sadistic as the criminals they hunt, and it firmly addresses the hypocrisy shown by students who protest against gang violence, when the drugs they purchase help to keep those same gangs in business.
But what, ultimately, is Elite Squad trying to say about the BOPE themselves? Is Padilha admonishing their fascistic tactics, is he revelling in them, or is he collapsing clumsily somewhere between those two stools? The film's lack of a solid, coherent viewpoint works against it, and there's really nothing here – in terms of storytelling or filmmaking – that distinguishes Elite Squad from other recent South American films that have covered similar territory, such as Carandiru and El Bonaerense. Of course, the picture looks particularly weak when held against its most obvious influence, Fernando Meirelles' City of God. That film wasn't perfect, but it told its story with a clear artistic vision and a bracing kinetic energy. In contrast, Elite Squad simply wants to pummel us into submission.
Posted by Philip Concannon
Labels: 2008 Reviews
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Press Center Daily News 2005 VERB GIVE 'COLBERT' ITS PATRIOTIC LOOK
VERB GIVE 'COLBERT' ITS PATRIOTIC LOOK
The Colbert Report, starring Stephen Colbert, is a half-hour program that spoofs mainstream political analysts such as Bill O’Reilly, Joe Scarborough and Chris Matthews. Its design embraces all things patriotic. Rather than recreate a Factor or Hardball design, Verb creative director Greg Duncan says, “We decided to amp it up and build Stephen into a fully-realized three-dimensional world of hyper-patriotism, replete with macho adjectives, a large squawking eagle and a giant, chrome-plated 3D ‘C’ for Colbert.”
The team started by shooting Colbert in a variety of cliched, news anchor-esque poses on a greenscreen stage.
“We brought in a jib arm to get some great angles and we put Stephen on a turntable,” explains Verb executive producer Bill Bergeron. “Stephen instantly figured out the comic possibilities of the turntable, like allowing his legs to spin a little too far as he spins around. Everyone on set was laughing for much of the shoot.”
Verb lead designer Andrew ‘Stubbs’ Johnston and designer ‘Be’ Chamlinaroen worked on designing the patriotic world. They designed and built elements using Apple Power Mac G5s, Adobe After Effects and Maxon Cinema 4D. Editing was performed in Final Cut Pro with Blackmagic Design hardware. The sophisticated CGI eagle, Colbert’s co-star and alter-ego in the show open, was created by Andreas Berner using Alias Maya on a Mac.
VES announces nominees for 18th annual awards
LOS ANGELES — The Visual Effects Society (www.visualeffectssociety.com) announced the nominees for the 18th Annual VES Awards. The yearly celebration recognizes outstanding visual effects artistry and ...
Ben Lock & Patric Roos to head Outpost VFX APAC
BOURNEMOUTH, UK — Ben Lock ( Star Wars Episode VII – The Force Awakens, Ready Player One ) and Patric Roos ( Avengers: Infinity War, Guardians of the Galaxy Vol. 2 ) have joined Outpost VFX (outpostvf ...
Canon introduces four affordable 4K pro camcorders
LAS VEGAS — Canon USA Inc. (www.usa.canon.com) recently announced four new additions to its XA Series of professional camcorders. The XA55, XA50, XA45 and XA40 are the first in the series to feature 4 ...
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22. Witch Hunt
Changeling: The Streaming » Story Archive » 22. Witch Hunt
The motley learns about Lady Helena's past, and try to uncover the traitor.
Original Air Date: March 4, 2018
Sunday, November 12th, 2017.
Terra's Glade, Homefires.
Lady Helena, Kyoko, Claude,
Sir Xaeron, Lord MacAllistar.
Scott, as Braum, for demanding the MacTruth, and receiving a MacDuel.
Diplomacy could lead to the downfall of a character today….
"I accuse you of being an associate of the known Dauntain, Zistor Flexx!" The Lady Helena calls down the Sovereign Art of Protocol, forcing all present to adhere to the rules of the court. Patches protests her innocence as Braum, still hidden with Veiled Eyes, circles around behind the assembled Kithain, getting ready to spring into action if needed. Sophia requests proof of any wrongdoing in the case of either Zistor or Patches: "she was unaware of why she was to assume control of the Spark", Sophia explains.
The Lady Helena brings forth a chair for the accused, and asks her about Zistor. The Dauntain are always branded quite obviously; has Patches ever seen anything of the kind on Zistor? When Patches defends the nocker, Lady Helena asks about the rocket: what is it that Zistor intends to do with it once it has been found? Unsure of Lady Helena's loyaties and motives, Patches neatly sidesteps answering the question, and the Lady Helena points to a Magic Motion Box. It turns out she has been recording footage in the Spark for almost ten years, and proceeds to show an audio-less clip of the two nockers working on the rocket's "battery" (which was only several days previous). Patches and Sophia are both shocked by this blatant violation of their privacy and the Spark's demesne, and they question what reason she has to suspect Zistor of anything given her association with the Red Branch.
Lady Helena dismisses the entire court, including her three warriors, much to the surprise of the motley. At Sophia's request, she tells her side of the Red Branch's Abford Pharma mission. After Kyoko was sent inside as a test subject, she entered to search the administrator's office. The rest of the team went to recover Kyoko but it would seem there must have been a traitor amongst them…. Both Kay and Celyan were mortally wounded with cold iron, but saved from true Fae Death by Braum, who killed them himself. "I did die," Helena tells them. "Only Braum was able to resist." The motley learns that, for the next 8 years, Lady Helena was kept in Abford Pharma as a test subject; Sophia senses an incredibly high Banality about her person, lending credence to Lady Helena's story.
Helena then tells them the reason she invited them to Terra's Glade: she believes that the rocket may have as its source a warlock, the Dauntain. "There's a traitor amongst us," she tells them, and since she believes it is not one of the Kithain before her, she wants them to find out who it is.
Returning to Homefires after explaining the situation to Kyoko, Claude, and Sir Xaeron, Patches decides that the first course of action should be the most direct. All members of the motley who were present at Abford Pharma must disrobe and present themselves for inspection, to see if they are hiding any suspicious marks. Sophia balks at the idea (naturally) and walks out, much to the relief of Claude. Kyoko also leaves, claiming to be "uncomfortable with distrust", but Braum speaks up for her, assuring the group that he has never noticed anything resembling the mark of a Dauntain on her. Claude, Patches, Braum, and Sir Xaeron all in turn disrobe and check each other in a bizarre scene, but find nothing.
That night, Braum anxiously awaits the return of Lord MacAllistar so that he can report his findings on Lady Helena. The leader of the Red Branch is shocked to hear that Helena is still alive, convinced as he was that he had "lost three in the mission". Braum pointedly asks Lord MacAllistar to explain why he didn't allow the surviving Red Branch members to return to search for the missing Helena, and then, summoning up his courage and hoping to catch him with his bluntness, asks Lord MacAllistar if he is Dauntain. The satyr of House Gwydion explodes: how dare Braum accuse him of something so vile? Drawing two rapiers, he demands a fight to first blood. Braum attempts to get Lord MacAllistar to understand his logic, but the satyr only seeks revenge. The two clash, and a slip on Braum's part leads him to get pierced straight through the shoulder. "Friendship may mend many wounds, but for tonight, you are not welcome in this office!" he roars.
Braum stumbles downstairs to the lobby, wounded in both shoulder and pride, just as Sophia returns from a shopping trip. She is concerned for Braum until she realizes that he did this to himself by acting foolishly. Braum refuses her offers to heal him and stumbles off towards the Games Room, holding back tears of shame. In the Games Room, he encounters a lonesome Patches, who cleans his wound while commiserating with the troll about trust, or, more specifically, how dangerous it can be.
Back in her quarters, Sophia discovers a small bouquet of flowers left for her with no note. She wonders idly if perhaps Kyoko, who had thanked her sincerely earlier for trusting her intentions, had left them, but decides to find out another day.
That night, all those Red Branch members still alive from the Abford Pharma mission sleep well… including the one who bears the mark of the Dauntain.
« 21. The Resistance
23. Salem »
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Game Journals »
Retro Encounter Podcast Thread
Author Topic: Retro Encounter Podcast Thread (Read 180515 times)
Hey everyone! We're doing our own game journal! ...sort of.
http://www.rpgfan.com/news/2015/3099.html
A new podcast approaches!
We'll play a new game every month, with three episodes per game. Episode 0 is a brief introduction, and tomorrow we'll have our first episode, discussing the early parts of Trails in the Sky! We want to talk with you about these games, and maybe even have you join us for our playthroughs. Chat us up here!
Salvum est Vita!
Re: Retro Encounter Podcast Thread
I like the idea. But you guys are just calling things "retro"whenever you feel like it.
I thought this was going to be replays of 8 and 16 bit classics. Trails in the Sky doesn't seem old enough to fit the bill. If you play FFXII or Tales of Vesperia and call it "retro"you going to have a lot of explaining to do to anyone who is over 30.
Probably still a great Podcast but I am a bit disappointed.
"This goes way beyond pumpkin spice" "Whale oil beef hooked"
Well, Trails in the Sky first came out in 2004, and that's over a decade ago.
But, more to the point, we want to hear your feedback as to what games you'd like to hear us play! So let us know! When we say retro, we mean 'older games' not 'only the oldest games.' The crew behind this show wants to have a lot of collaboration with the community as to the form and path of the show, so if you want to see 16-bit games (which we definitely already have plenty of on our list), tell us!
DaviKaze
Quote from: glassjawsh on May 05, 2015, 06:37:51 PM
Most of us are that age ourselves, so we definitely understand the sentiment. But yeah, definitely just let us know what your the most interested in, and we'll be sure to prioritze it! We hope to open the game selection to listener vote very early on.
Not even Jupiter can find a missed opportunity.
Off the top of my head for each of the "retro"consoles (fifth generation back):
1. Panzer Dragoon Saga - Saturn
2. Breath of Fire 3 or 4 - PSX
3. Paper Mario - N64
duh. Lunar 2: EB - Sega CD (or the PSX version)
4. Earthbound - SNES
5. Shining Force II - Genesis
6. Legend of Zelda - NES
fuck it. also wouldn't mind listening to you guys try to grind on through:
Symphony of the Night, Parasite Eve, Tales of Destiny II (the NA version for PSX), Vagrant Story
Lufia II, Super Mario RPG or Secret of Evermore.
Tales of Destiny II (the NA version for PSX)
You probably mean Tales of Eternia.
You, sir (or ma'am) have impeccable taste! There's only a couple of those not on our list already, so I'll make sure to add them. Really excellent suggestions!
IhaveFURY
Draw! Monster cardo!!
I'd be so down for a Parasite Eve discussion it's not even funny. Excellent suggestion, sir.
Wild Armor
Quote from: Annubis on May 05, 2015, 07:36:05 PM
My first, and favorite, "Tales of" game. I would play this in a second.
I've never played a Parasite Eve game, so I wouldn't object to that. Also, I love this list. MOAR.
It was still called Tales of Destiny II when I played it as a freshman in college. AND it came out before the Japanese ToD2. So I always felt like calling it Tales of Destiny II is still ok if you make note that you are talking about the North American PSX version. Also there are a lot of subtle (and not so subtle) differences between the game I am talking about and the Tales of Eternia that came out on PSP.
It is ALSO my favorite Tales game by a WIIIIIIIDE margin.
« Last Edit: May 05, 2015, 09:13:02 PM by glassjawsh »
You guys have also inspired me to make a game art podcast.... Projected to be listened to by about 2 followers over the span of ten years. Or lemme gest star as RPGFan's most obnoxious and irritating stereotypically-rambling-female award poster.... Bah. Point is, I've really enjoyed these lately and get happy when they're up, keep t up. Keep up the good work, I'll probably be listening in on this while I do some urrtweerk [artwork].
#notintoxicated
Electric Mayhem
This was a concern that came up when we were having discussions as to what to call the podcast. We ultimately decided on Retro Encounter because 1) it looks / sounds good alongside Random Encounter and Rhythm Encounter; 2) we are more than likely to concentrate on games that are 10+ years old; and 3) it was probably the favorite suggestion among all the options.
Trails in the Sky was chosen as the first game because it was the suggestion that garnered the most interest after an internal vote. The second game is another game from the early 2000s - we don't want to put ourselves in a box by ONLY playing RPGs from the 80s or 90s, even if it makes the podcast's title a little misleading. And honestly, "retro" is in the eye of the beholder.
http://therealmonsoon.blogspot.com
Quote from: Monsoon on May 05, 2015, 11:26:04 PM
And honestly, "retro" is in the eye of the beholder.
So you're going to play the Eye of the Beholder trilogy?
Apparently they're spectacular!
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Lost world… found? April 28, 2009
E. coli outbreak leads to massive flour recall July 1, 2016
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Upfront (One Way or Another #1) by Jade Cain
July 20, 2014 Erotica, Interracial, Jade Cain, M/M, Romance, Series: One Way or Anotherselkieadmin
Ethan Kovac loves being an actor, loves his two co-stars on his new sitcom One Way or Another. He and Samantha Jensen got their start as kids together, and now she’s a superstar. Isaac Duncan is a great guy, but he’s tall, dark, and unfortunately for Ethan, straight.
Acting’s the fun part. The promos make him crazy, like having to attend the network’s ‘upfront’, where they sell advertisers on new shows. But at the after party, when he and Isaac start bantering for the reporters, his thoughts take a turn for the naughty, especially every time Isaac wraps his arm around him for photo ops.
One steamy encounter in a restroom and Ethan discovers that Isaac isn’t completely straight… but is it a one night engagement, or does Isaac have more on his mind than the latest script?
On Sale Now:
Amazon • Barnes & Noble • Smashwords • Kobo • iBooks • All Romance EBooks • Selkie Sea Press
Continue reading Upfront (One Way or Another #1) by Jade Cain →
Pilot (One Way or Another #2) by Jade Cain
September 3, 2014 Erotica, Interracial, Jade Cain, M/M, Romance, Series: One Way or Anotherselkieadmin
Big news–the network picked up One Way or Another. Big rumors–the set is full of the tension between its two leading men. Isaac is determined to keep his mind on the job, but Ethan keeps tempting him to bad behavior in quiet corners and secluded places around the soundstage. For a guy who wants to stay in the closet, Ethan takes too many risks, and Isaac’s getting nervous.
Worse, it’s not just about the sex anymore. What was supposed to be a quick impulsive fling is threatening to turn into more–Isaac can see it (and feel it) every time he looks Ethan in the eye. When Ethan wants to take a big step, is Isaac ready?
Continue reading Pilot (One Way or Another #2) by Jade Cain →
Hiatus (One Way or Another #3) by Jade Cain
Have you heard the latest? Gossip sites are posting stories about the antics from the set of One Way or Another. Rumor has it someone’s been having sex in their dressing room; it’s only a matter of time before someone’s posting photos, or even better, a sex tape.
Isaac is hounded by paparazzi who all want to be the one to confirm the stories, and a hot late night phone call sees both Ethan and Isaac about to confess more than their fantasies to each other.
Rumors are one thing, but when Ethan overhears a conversation on the set, he learns just how much Isaac is risking being with him: his career, his reputation, everything he’s fought for all these years. Can Ethan keep asking that of him?
Continue reading Hiatus (One Way or Another #3) by Jade Cain →
Sweeps (One Way or Another #4) by Jade Cain
On the eve of awards season, things are still in turmoil for the stars of One Way or Another, despite Ethan’s best efforts to calm the waters. Ethan’s out of the closet, Isaac’s dating an old flame, but Samantha’s bad behavior on the set is the talk of the town.
Though it may be down Sam to make Ethan and Isaac sit down and talk things out, nothing is ever that easy. Reunited in a steamy, illicit encounter at a party, Ethan and Isaac end up overhearing the truth behind Sam’s outbursts on the set.
When the boys discover just how bad things have gotten, will they be able to help Sam? And have they really resolved their differences, or was this a one-night-only engagement?
Continue reading Sweeps (One Way or Another #4) by Jade Cain →
Finale (One Way or Another #5) by Jade Cain
It’s been a roller-coaster first season for the cast and crew of One Way or Another. The first nominations of award season are promising, especially for Ethan and Isaac, but the harassment Sam’s facing on set is only getting worse.
The three co-stars come up with a plan that will not only end the harassment, but leave Ethan and Isaac free to go public with their love for each other.
Then an impetuous move from Ethan puts everything at risk: their plan, their jobs, and even his relationship with Isaac. Can one kiss bring down three Hollywood careers?
Continue reading Finale (One Way or Another #5) by Jade Cain →
What Not to Do on a Stakeout (For Queen & Country) by Jade Cain
September 8, 2014 Erotica, Jade Cain, M/M, Series: For Queen & Countryselkieadmin
Aidan Blake and Nick Kaplan are flatmates, nothing more. Both agents with Great Britain’s MI-5, Nick moved in when an injury threatened to push him out of field work.
The problem is, Nick can’t stop thinking about how sexy dark-eyed, dark-haired Aidan is. And now they’re stuck together on a stakeout, alone for hours in an empty office.
When Aidan offers an intriguing cure for boredom, Nick can’t refuse–but maybe he should check his surroundings first…
For Queen & Country, the newest series by author Jade Cain, combines intrigue, action, sex, and humor with two unforgettable (and sometimes irresponsible) British spies, Nick Kaplan and Aidan Blake.
Buy "What Not to Do on a Stakeout":
Amazon • Barnes & Noble • Kobo • iBooks • Smashwords • All Romance EBooks • Selkie Sea Press
Undercover Games (For Queen & Country) by Jade Cain
September 8, 2014 Erotica, Jade Cain, M/M, Romance, Series: For Queen & Countryselkieadmin
Nick Kaplan and Aidan Blake are experienced secret agents, stars of MI-5… or they were until they moved in together and became lovers all in one fell swoop. Now, before they have a chance to work out what’s happening between them, they face their hardest test yet: keeping their hands off each other when they go undercover as strangers. Someone is selling deadly secrets to Great Britain’s enemies and a terrible chemical weapon is about to fall into the wrong hands.
Nick and Aidan are ordered to the scene of the crime—a government lab—to track down the traitor. Faced with the prospect of a long stay in a remote Northern corner of England, Nick offers Aidan a bet: whoever breaks their self-imposed celibacy first by instigating sex will pay the price when they return to London. It’s all fun and games until they actually have to tough it out. If they can’t make this work, all of Great Britain could be at risk, but neither of them can think clearly when they have to be apart.
One Way or Another: The Complete Series by Jade Cain
September 23, 2014 Erotica, Interracial, Jade Cain, M/M, Romance, Series: One Way or Anotherselkieadmin
Wake Me Up by Jade Cain
October 6, 2014 F/M, Jade Cain, Romanceselkieadmin
He kept her alive… can he make her feel alive?
Journalist Casey Mallory survived an ordeal like no other: taken hostage by Islamic militants in Iraq, they not only stole her freedom and her sense of security, but they brutally severed her left hand on-camera. She would have died if not for Ian Bradley, the undercover operative who rescued her.
A year later, she’s returned to Iraq with a camera crew to tell her story and face her fears. Ian insists on coming as her security, but Casey wants more from gorgeous Ian than his protection. She craves the touch of his strong, lean body, needs him to make her feel like the woman she was before the kidnapping.
If they survive a second time, she’ll do what it takes to get him into her bed…
Taking the Commander by Jade Cain
October 6, 2014 Erotica, Jade Cain, M/Mselkieadmin
The war-torn desert of Iraq is no place to get distracted, but Captain John French of the Royal Marines can’t help but notice the sexy commander on loan from the Navy Special Forces. SBS Commander David Cole is an arrogant bastard but he’s also the most gorgeous thing John has seen in ages. When circumstances push them together and a mission nearly goes wrong, John can’t decide if he wants to punch the Navy man, or screw him. Maybe both.
“Taking the Commander” is a Double Alpha story, where two alpha males are better than one.
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Category: Oakley Radarlock Photochromic
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With 4 recline positions, you can keep your child comfortable, while the InRight LATCH system makes installation easy with a one second attachment. The seat is side impact tested, and SafeSeat Engineered, giving you peace of mind. With all these great benefits, in a sleek space saving design, the SlimFit is the perfect car seat! read more.
The Milwaukee Bucks player and NBA MVP said he hasn to the coach about which position I be playing the important thing is to play. I play the 1 (point guard) or the 5 (center), I don care, Antetokounmpo said. A basketball player. A school board voted Tuesday to move ahead with a plan to build a new school in place of the 82 year old building, instead of preserving a portion of the iconic building and building new structures around it.The board’s vote was unanimous in favor of demolition of and full replacement of the school.”This is about what our students deserve, need and have long waited for,” said Superintendent Francisco Duran.”Because we are taking a pool away from you we can give you a pool back,” SDA CEO Charles McKenna said to loud cheers from the audience. McKenna said the pool will be funded through the original project budget.The board was faced with two options to demolish the school and replace it, or attempt to preserve iconic portions of the building and build around it. An issue was raised with the latter option after structural engineers hired by the SDA determined it would be extremely difficult to preserve the specific portions of the building because of the state of decay of the building and the questionable structural integrity that that portion could stand on its own.A site concept plan prepared by the SDA showing its design concept plan for the new Trenton Central High SchoolThe SDA gave a lengthy presentation to the board about the structural issues and the different options before they were asked to vote on one of the two.The members of the public who came out to speak about the project were mostly in support of replacing the school with teachers, parents and students speaking out.Junior Tyshona Robinson said her memories of the high school are those of “disgust and disappointment” because of the state of the building.
“We feel like we have been able to address our needs, both on offense and defense, as well as specific positions,” Polian said. “We also feel like we have improved the overall athleticism of the team. Lastly, we have some members of this class that come from places outside of our normal recruiting territories.
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MacMillan, S. Beswick, T. Curtain, D. But one day out of the blue, he was laying on the couch with my brother and i walked by. I guess he didnt recognize me at that point and he launched at me. Luckily i was not hurt because of quick reaction. It said legal procedures obliged USADA to fulfill this demand in cases “where no hearing occurs. ” n n n nThe International Olympic Committee said Friday it will await decisions by USADA and UCI before taking any steps against Armstrong, who won a bronze medal at the 2000 Sydney Games. Besides the disqualifications, Armstrong will forfeit any medals, winnings, points and prizes, USADA said, but it is the lost titles that will be part of his legacy.
The onion or the Allium cepa of the Allium family loses out to its close cousin the garlic in terms of importance of health benefits because it has been poorly researched. As for me, the onion is one indispensable item in my kitchen and I cannot imagine cooking without onions. They make the base of my curries and add that extra zest to my main dishes.
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It doesn matter who “initiates” the story. The point of the story is for the team to understand the business value of the story. Sometimes the business value is to improve the customer experience, sometimes it is not. I taken a lot of courses that I haven fully completed and still got a lot of value out of them. I would venture to guess that cheating is perhaps lower currently with the students who complete MOOC because the fact that there is no current incentive to do so. Also it not that it isn rigorous either at least for some of the EdX courses they are almost 1:1 translations of the OpenCourseWare versions, which themselves are just the actual classes they teach at MIT.
Dan Niebuhr, Colorado Springs, Colo. (Sunkist Kids); 3. Ethan Bosch, Colorado Springs, Colo. And finally, not so much a point of trivia, but a sad postscript. Kay Kendall met and fell in love with film star Rex Harrison in 1955. Harrison was married at the time of this affair to actress Lilli Palmer, but the affair persisted.
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I don’t think your characterization of how WB plays is very based in fact. He plays to win. Yes he does get his 10/10/10 every game and his teammates support that but they support that cause his motor is insane and like all of those role players wouldn’t be in the league right now if it wasn’t for WB, minus Adams and Schroeder.
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By then, David Checketts’ son had tweeted that Checketts, the old Garden czar, was trying to bail Oakley out of jail. The old wingman, No. 34, he needed the help this night, probably needed to sleep it off. The pristeen and delicate wilderness values of these islands must be preserved for future generations. Camping is limited to four campsites per island, and four people per site. Pit type toilets are available..
“There would be police officers all around Queensland and Australia who have gone to difficult and dangerous incidents were they could have very well suffered the same fate as Damian. “It is hard, I like all other police, have taken this very hard as I know it can and it does happen. “We all take this time, our prayers and our thoughts are with Damian and Sonya and those two little kids who will never have a father.” Senior Constable Leeding police colleagues, co workers and friends who knew him best gathered at the Coomera police district office and station yesterday afternoon to remember their fallen comrade.
Bayer is making a crystal aspirin that dissolves instantly on the tongue, which gets into your system twice as fast. Keep it at your bedside in case of a heart attack. If you are awakened at night with chest pain, take 2 of these aspirins immediately, then call 911.
Coaches, including Stan Van Gundy and Steve Kerr, are engaging in passionate arguments about what Trump winsays to the league, its players, and the country. Smith has publicly reckoned with about the election. LeBron James and Doc Rivers have been passionate but conciliatory, urging the nation to come together and keep working for progress despite disappointment in the results..
False. As Whitney Way Thore, star of TLC “My Big Fat Fabulous Life,” said in her response video, cannot tell a person health, physical or otherwise, from looking at them. We have anecdotal and scientific evidence that fat shaming of the sort Arbour engages in fat people, blaming them for their weight, equating fatness with moral and health failings, expressing sheer disgust for the existence of fat people actually have the opposite of Arbour intended effect and cause people to gain weight.
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The code hopping coach said her Tigers side had been focused on perfecting the basics for the opening phase of the season, with the results on show in the last few weeks. “Now we move on to some more structured things, working with our goalies, defenders and mids in their specific areas,” Peake said. “Just angles that good passes come from and good positions for the goalies to get into.
The meeting, held in the Playhouse, drew a large crowd of members who voted in a new slate of officers, including a new president, Amy Lyn Van Londersele of Tweed. Van Londersele has served as vice president for the past two years and starred as Annie Oakley in last year musical, Get Your Gun. She also directed this year musical, Last Five Years.
As consumers grow increasingly aware of antibiotics, glutens and preservatives in their own foods, they have turned their eyes to the labels of their pet’s food as well. With approximately 6 8 dog food aisles and 4 6 cat food aisles in the typical pet supermarket to peruse, pet owners attempting to decipher the quality of the ingredients in the packages find themselves overwhelmed by pricey holistic recipes and life stage formulas purporting to contain organic ingredients. But what do these promises on the label really guarantee?.
This is a dual core 13″ Mac (purchased in March 2018) with 16 gb ram. I think it has 500 gb storage. You could get by with 250 gb. Instead, she chose a special item from her home for each of her family members: an old butter churn, an antique clock, a handmade quilt, a piece of framed embroidery or a painting. She wrote a short history of the item and included it with the gift. Her family was delighted, and I thought it was a wonderful way to be sure that special items went to the intended recipient..
Air Force and has been serving most recently as vice commander of the Air Force Expeditionary Center at Joint Base McGuire Dix Lakehurst in New Jersey. She is retiring after 27 years with the military. She holds bachelor degrees in mathematics and computational mathematics, and three master degrees..
He definitely wants to play for us.” . Philadelphia 76ers GM Jimmy Lynam, holding the No. 2 pick in the June 30 draft, is skeptical about the Golden State Warriors’ ability to trade up (from No. Had a heck of game on both ends of the floor, Nets coach Kenny Atkinson said Friday. At the end, he made (Tim) Hardaway work for his shots. He was our leader (Friday night).
Features of the Thule EnRoute Backpack 20L Protect a 14in. PC or 15in. MacBook and 10in. Maui HT High Transmission Lens is suitable for variable and low light conditions. HT boosts colors, contrast, and depth perception, and delivers the most visible light of all Maui Jim lenses. Maui Rose is a high contrast lens with a subtle rose tint.
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I seriously considered quitting my job because there were 3 pregnant women that I work closely with. It gets better with time, but sometimes I walk the other way or avoid social events with my pregnant friends. The worst is the comments from other people about how cute their bellies look or how excited they must be.
I had never done Broadway before, and I didn’t know the discipline it would take to do eight shows a week. But I was surprisingly equipped for it, and it changed me for the better. It was learning how to trust the moment and trust the work I put into it.
The change in OAD was $3.6 trillion dollar duration years. To put it in perspective, the Chinese bought $600 billion of Treasuries and Agencies during that time period, with an aggregate duration of $1.2 trillion. Economy. I was a bit over the seventeen and a quarter mark, but I did volunteer and went to Adastal House I think it was, in London, where I was I didn’t have to move to London, I travelled to London each day for three days, and I did my attestation there. That was very simple for anyone just left school, mathematic test, intelligence test, and an essay on a choice of subjects, which I chose the importance of Gibraltar, a medical and I was duly accepted into the RAFVR, RAFVR [emphasis], as a pilot under training. Was given a little lapel badge RAFVR and a number 1391635AC2, pilot under training and sent home to be called up [emphasis] when necessary, when ready.
He was Methodist and a Mason. Survivors: wife, Martha; sons, Kenneth E. Jr., Jeffrey Allen, both of Du Pont; sister, Mary Ella Scott, Madison, Ind.; three grandchildren. Due to legal reasons, the movie version of Irving Berlin’s rootin’ tootin’ musical “Annie Get Your Gun” has been unseen since 1973, when it was yanked out of circulation. This week, on the 50th anniversary of its original theatrical release, the movie will again see the light of day. Warner Home Video is issuing a special edition video (1950, G, $20) and DVD (1950.
It always amazes me to read articles like this. How come I don need more than 3 hours of sleep a day and its been like that for over 15 years now?I sleep “late hours”. I go sleep around 8am and wake up around noon. Appropriate for ages one and up. About GUND: For more than 100 years, GUND has been a premier plush company recognized worldwide for quality innovative products. Building upon our award winning and beloved plush designs, we continue to practice innovation by constantly developing new original and licensed designs to appeal to the next generation of customers.
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There probably isn’t a team in the league as well set up to divest all assets as the Denver Nuggets . The combination of a deep roster of mismatched parts and an underwhelming win loss record makes almost everyone on the team expendable. If you have a need, chances are the Nuggets have a player who can (somewhat) satisfy it.
A man described to a jury how he found the body of 14 year old murder victim Viktorija Sokolova in Wolverhampton’s West Park.Daniel Squire said in a statement read to the city’s crown court by Ms Louise Oakley, prosecuting, that he was on his normal morning walk with the family dog when he stumbled on the gruesome scene at around 7am on April 12.He explained: “As I approached a circular area with numerous benches I saw what appeared to be a body.”I was aware there had been a fun fair in the park and believed somebody had set up a prank and it was a blow up doll.”I walked away to the left and took a path that took me back to the circle. The body was on a bench near by.”It was definitely a deceased body.”I rang the police. The closest I came to the body was four metres.
Outlook: A strange thing happened to Funk this season. She threw a field hockey party, actually varsity tryouts, for 21 freshmen and only four of them showed up. That does not bode well for the future, especially because Funk had worked hard at middle schools in the area to encourage youngsters to come out for the team.
McCain Middle School, Payette. Madison Junior High School, Rexburg. Magic Valley Alternative High, Twin Falls. From fun, brash actioners like The Incredibles and Cars, to the quirky weirdness of Monsters Inc. And Ratatouille, they stood head and shoulders above the fart gags and wisecracking donkeys of Dreamworks, their nearest rival. Not forgetting, or course, their award winning animated shorts such as Tin Toy, Geri Game and last year La Luna..
In the rebuttal to the Journal article provided to the judge, PG acknowledged that it had proposed replacing 60 towers on the line that runs through Butte County where the fire started. But the company said that was for work required to meet federal standards and that the scope of the project didn’t target the particular transmission tower where the power line failed and the fire started. It also said that from 2014 to 2017, only a small portion of the fires caused by the utility were sparked by transmission lines..
I recently took a trip to Oakley headquarters in California, which offered me an excellent platform for discussing what makes sunglasses more than just a summertime accessory. By talking with members of the company research and development team (and even a few scientists I tried to distill the broad world of sunglasses into a few key and comprehensive guidelines for anyone looking for a perfect pair one that will look good and effectively keep the eyes safe. Ultimately, three factors stand out from the rest: lens quality, impact protection and fit..
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Cherished Pa of Joel (Jen), Connor, and Kelsey (Keith); Andrew, and Emily (Owen); Nolan (Harman), and Joanna (Matt). Great grandfather of Lily, Ivy, and Oakley. Howard was predeceased by his brother Melbourne (the late Wilma), and brother in law John Mark (survived by Judy).
Cosmetics Beauty Accents > Saks Fifth Avenue > Barneys. Bkr. Made with durable stainless steel, this metal water bottle has an easy to grip design that holds 16 ounces of your favorite cold beverage. De son ct, le public des petites villes voulait savoir ce qui se passait dans les coulisses. On prenait parti, on cabalait avec passion. Des oisifs crivaient des pamphlets pour ou contre les acteurs qui se dfendaient de leur mieux contre la malignit et la curiosit, quelquefois relevaient le gant de l’adversaire et transformaient leurs trteaux en tribune.
Washington and Iron counties were accommodated on some requests putting Cedar back in a region with the St. George schools for all sports and moving Canyon View to 3A for football but it means they have seven schools, and only four qualify for the playoffs. The three other non football 3A regions will qualify four of five schools for the playoffs..
Would I get out of this if I were an incel? I consider that my hypotheses about the world are wrong and try a different strategy. If I looked outward my whole life, I start looking inward and try to improve myself. When it comes to partners, I look for the most attractive partners that would sleep with me, even if that not that attractive.
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Det. Wendy Morton was patrolling northeast Baltimore on the April day the lonely widow called 911 because she couldn’t see. Morton’s routine stop led to regular visits with honey doughnuts, to midnight phone calls for “girl talks,” to dances around the house at which a great grandmother showed a 35 year old how to shimmy to Marvin Gaye..
Browning, who developed an automatic rifle for GIs, and John T. Thompson, whose submachine guns were popular with gangsters, at least in the movies. There’s Napoleon’s ornate rifle and a whole room devoted to the guns of Teddy Roosevelt, including one with the presidential seal, another used on safaris and one that was carried by a comrade on the Rough Riders’ charge up San Juan Hill..
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Was the current assistant coach, and the athletic director highly recommends him, Baker said. Is also a teacher in the middle school and has been very involved with boys basketball over the years. A 2002 graduate of Central who played varsity basketball, football and baseball during his high school days, has served as a coach in various capacities in the Spring Cove School District.
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Besides the All Star ballot, there’s somewhere else you won’t find the name of Shawn Marion . In trade talks for Atlanta’s Dikembe Mutombo. Marion was among the Phoenix forwards mentioned when the Mutombo rumors started weeks (months?) ago, but he has since become the game’s best rebounding small forward.
It seems that the open hand of Christ symbolizes peace and the five wounds of Christ. Other icons have the finger placement in a slightly different position on Christ’s right hand and have a somewhat different meaning. Both Greek and Latin variations and their meaning can be found here: What is the significance of Christ’s hand gesture (thumb and two fingers up, two fingers down) in Christian art?..
5. Once you stir the powdered spices in the tomatoes, increase the heat back to medium. Stir regularly with your bare hand, very important! and continue cooking the spices until the oil separates from the tomatoes. Thank you for the excellent report regarding the use of electric shocks on disabled students. Decades of scientific Thank you for highlighting the terrible techniques this MA school uses against its students. I am imagining the school is receiving public funding.
Topical TreatmentWhether you have oily or dry skin, one of the major medicinal uses of aloe vera gel is to revitalize the skin. Just cut it into big pieces and rub it on the skin. Use aloe vera to relieve pimples, eczema and any other skin ailments.
Includes: water/cooking pan, juice pan, strainer/steamer pan, lid, and hose with clamp. Item can be used separately as a stockpot and steamer. Induction compatible and works on gas, electric, glass, halogen, ceramic, etc. I like to distil the idea and form of a cloud to its linear essence, to use this as a silhouette with a great deal of lyrical movement. Pendant calls to mind Art Deco styles European jewellers in the 1920s were hugely influenced by Chinoiserie and motifs, including clouds and dragons, along with Indian and Persian culture. Was a desire to bring something says Warren.
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Size: 8. Color: Green. Gender: Male. Turning away, a flash of motion caught the edge of her eye. A lone man, dressed in a military uniform was making his way to the exit, surreptitiously ignoring the joyous reunions happening behind him. That gait was so familiar, the broadness of those shoulders, the color of the dark hair.
If I can categorize this manga, I think Strobe Edge would belong to the rarest of gems. It tells the story of Ninako Kinoshita (main female protagonist), who falls in love with with a guy who already has a girlfriend (Ren Ichinose, main male protagonist). Ninako realizes her feelings for Ren early on but decides to keep it hidden, but you know, things just tend to happen (sorry won’t spoil!).
: The Mudbugs and Thunder will meet for the fifth and final time this year Saturday night here in Bossier City in the conclusion of “Pink in the Rink” weekend. The ‘Bugs won the first three meetings between the teams this year, but Wichita bested Bossier Shreveport 4 2 in their last meeting on February 5. The Thunder has lost four straight since a three game winning streak earlier this month..
Malone led the Jazz with 23 points and 15 rebounds, but in the end he was left to answer questions about the missed free throws. He got to the line after Bulls forward Dennis Rodman wrapped his arms around Malone’s waist as the two scrambled for the rebound of a missed jumper by Stockton. But with the game tied at 82, Malone was unable to come through..
The storm that wipes out the pathetic little thing you call your DR character. It fucking dead, kid. I can be anywhere, anytime, and I can kill it in over seven hundred ways, and that just with my brawling ranks. Shoko Nakagawa, who plays Joy in the upcoming film, praised the beautiful waterways and accordion music in the 2002 film.Miramax Films, which released the film in North America, describes the movie’s story:Famous Pokmon trainer Ash Ketchum is en route to a special water race for Pokmon in Altomare with his loyal companion, Pikachu. But when they arrive, they discover there’s bigger game afoot than the race. Annie and Oakley are a pair of female villains determined to steal the all powerful jewel known as the Soul Dew.
Joseph by the Sea, and choir director at St. Patrick’s Church. In July 1974, at the age of 41, he died suddenly of a heart attack while re roofing his brother’s house.. At the centre of the crisis, in Butembo, Stewart met one recovering and stoical Ebola patient, Kambale Moise. His brother had contracted the disease and passed it on to his visiting father, who took it back to Moise’s family. Moise’s wife and three children died.
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Jenkins a officiellement sign pour la r du deuxi opus en septembre 2017. Elle a imagin l’histoire avec Geoff Johns, et ils se sont ensuite associ Dave Callaham pour r le sc En mars, Jenkins a annonc que la “tr talentueuse” Kristen Wiig avait rejoint le casting pour interpr le Dr. Barbara Ann Minerva, alias Cheetah, une arch britannique qui se voit conf une force et une vitesse surhumaines par le dieu v Urzkartaga.
King Magnus ‘the Good’, Harald Sigurdsson’s nephew, destroyed Jomsborg in AD1043, ‘killing many, burning and levelling both the stronghold and the land around, wreaking the worst havoc’. The core of the membership had disbanded a lot earlier, perhaps shortly after the death of Jarl Sigvald around AD1010. Survivors of Magnus’ attack are said to have left with Sigvald’s brothers Heming and Thorkell ‘Havi’ (The Tall) for England with Svein ‘Forkbeard’ in AD1009.
Lastly, with the choices above you can now have your own wall mounted garage shelving systems. You just have to decide whether to buy at online store or any department store. If you will buy from an online store, make sure that it is credible. (the Knicks) lose, they only point at us, never point at Patrick. Patrick was our leader as far as press and people who are watching TV, but the Knicks were made of a lot of tough guys and a lot of heart. I think that sometimes we let our heart get in the way instead of playing the game Patrick could have been more vocal for the team, but he wasn I think that hurt us a little bit.
The NPV would mean every vote counts in every state. No voter can be written off as insignificant. One person. Back Doctor Alvin can help you to get back to the ground again. Choose only an accredited sports chiropractor in case your injury is sports related. Ice and rest can just give you little help on the event of sports injury.
A Look BackThe game of school is underway and all the players are well practiced. This was the feeling I had when I faced teaching Shakespeare’s Twelfth Night to an eleventh grade honors class as a student teacher at Columbia High School. Reading The Passionate Teacher, by Robert L.
That would have been four 30 point games of his past eight: It isn just a coincidence that the Raptors have a somewhat stunning, almost playoff ready record of 6 7 in games in which Bargnani has started. When he hasn played, they haven won. That makes this his team in a way it has never been his team much as he wanted it to be last year before..
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You are here: Home / Gallery / Indie / Show Review / Lil Baby Dazzles A Sold Out Crowd At The Fillmore
Lil Baby Dazzles A Sold Out Crowd At The Fillmore Reviewed by Kris Engelhart on May 1, 2019 .
The New Generation Tour Brings A One Of A Kind…
Lil Baby Dazzles A Sold Out Crowd At The Fillmore
By Kris Engelhart 829
Tags: 42 Dugg, Blueface, Charlotte Music, Drip Too Hard, Fillmore Charlotte, hip hop, Jordan Hollywood, Lil Baby, Live Music, Live Nation NCSC, Marlo, My Dawg, rap, Rap Scene, Renni Rucci, Shutter 16, Thotiana, Twit from the Pit
The New Generation Tour Brings A One Of A Kind Sonic And Visual Experience To Charlotte
Atlanta rapper Lil Baby is out on the road playing to sold out crowds all over the country on the New Generation Tour and here in Charlotte, we were lucky enough to be included as a stop on the tour. A full lineup of rappers is coming along for the ride including Jordan Hollywood, 42 Dugg, Marlo, Renni Rucci, and Blueface. This is definitely one of the must-see tours of the concert season and shows are selling out quickly so be sure to snag your tickets as soon as you can.
When I arrived at the venue, the line was already snaked around the block as fans were clamoring to get in and grab a spot up close to the stage so they could see their favorite artists in all their glory. First up on the evening’s bill was rapper and singer-songwriter Jordan Hollywood. Hailing from Broward County, the same area that produced the likes of Kodak Black and Lil Pump, Jordan is on his way up. Taking his stage name from a childhood football team nickname, Hollywood has worked with some of the best and brightest stars on the scene. After being kicked out of middle school, he visited a music studio at age 13 and found his true passion.
Not only is he a talented rapper, but Jordan Hollywood is a gifted songwriter. It’s something that seemingly comes easy for the young man, crafting songs for Jason Derulo and French Montana and ghostwriting for many, many more. His set was a fun way to open up the evening as he appeared on stage with the requisite DJ as well as a drummer. He had a great stage presence for an up and comer and put on a good show especially during his hit single “Trill Shit.” It will be interesting to see where he will be in a few years after he gains more of the all-important tour experience.
Detroit rapper 42 Dugg was up next and quickly worked the crowd running from one side of the stage to the other as the video screen behind him lit up emblazoned with his name. Dugg is probably best known for his Young And Turnt release and the song “The Streets” and the crowd was eager to interact with him and get things going.
Unfortunately with so many artists on the tour, there was only time for a few songs and his set was over too soon for my tastes.
I would definitely be interested in seeing him in a club setting with a chance to hear a full set. Perhaps another time, as I’m sure 42 Dugg will be out making music and hitting up Charlotte again soon.
Taking the stage next was Marlo, Atlanta rapper and childhood friend of Lil Baby. Marlo is fairly new to the rap scene but has been making music for a long time. He is already posting huge numbers on his social media accounts so It should only be a matter of time before he is taking his career to another level.
Again, his set was short but he knew how to make the most of his limited time and had the crowd up front with cellphones up and out bouncing along. Head on over to his socials and check out “Thinking Out Loud” or “Shootin’ Shit Up” to get a feel for what Marlo has to offer.
After a short break, it was all about girl power as female rapper Renni Rucci came out hitting it hard. I normally try to not point out that an artist is female, male, or whatever but in this case, I think it’s warranted.
With a few exceptions, hip-hop and rap are still very much a male-dominated world and it was fantastic to see a female artist come out and simply own the stage.
Rucci rapped, danced, and killed it, taking the audience on an adventure they will never forget. She is a true rising star and has released a few singles “Act Funny” as well as “Surgery” in anticipation of her big May release Big Renni. As the only female rapper on the tour, the girl’s got balls, (well, you know what I mean), and earned her spot with pure talent.
L.A. rapper Blueface was the final act on the undercard of the evening and man oh man did the crowd ever love him.
Everyone’s cellphone was lit up and in the air, recording all the action of his set. Blueface’s career really took off with the release of his 2018 mixtape Famous Cryp and he also went viral as an internet meme. His song “Thotiana” was a huge hit and his first song to crack the Billboard charts.
Blueface is a master showman and also used social media to his full advantage, snapping pics on his phone and taking a video of the crowd as he screamed, “we’re going viral tonight Charlotte.”
It was a fun set and when he ripped off his shirt to reveal his chiseled abs, I thought a good portion of the ladies around me were going to swoon. This was an act that would be tough to follow. Luckily, the main event, Lil Baby, was up next.
At this point in the evening, five rappers had graced the Fillmore stage; an entertaining night for sure but so far, nothing earth shattering or life changing. That was all about to change as Lil Baby was getting ready to take this party to the next level. When the venue lights dimmed, the huge LED screen at the rear of the stage lit up with the name Lil Baby and four dancers came out amidst plumes of smoke.
This was simply the beginning of one hell of a stage show that was in store for us. Atlanta rapper Lil Baby came out and the crowd went absolutely nuts. People were jumping, dancing, screaming, singing, and offering up marriage proposals as well as some things not safe for work. What a show this was turning out to be! The LED screens constantly changed ranging from pictures of Lil Baby to images of money or police vehicles.
Plumes of smoke rose up from the front of the stage, enough to make any metal band giddy with excitement. Did I mention the lasers? Oh yes, there were lasers. Think Trans-Siberian Orchestra style lasers, the kind that shoots down over the audience in glorious colors of green and purple and white and blue.
Through it all, Lil Baby performed his butt off, rapping, dancing, styling, and acknowledging the fans. His DJ was smooth and his raps were seamless, flowing like money out of an ATM. Every song was extremely well done and in unison with all the visual effects. This was by far, the best rap show I have ever seen and I can safely say that most of the sold-out crowd would agree.
If you are a rap fan, DO NOT MISS THIS TOUR. Forgive the capitals, but you really don’t want to miss this one and if you’re a casual fan, this would be a great way to foray into the world of rap and hip-hop. Fans were treated to tremendous performances by a bevy of artists all capped off with the incredible show put on by Lil Baby. Shows are selling out so don’t wait on tickets. Get them while you still can. Click here for ticket information.
See full gallery of the night here!
Catch Lil Baby:
Lil Baby & Friends
Thu 7 PM CDT · 1,323 guests
Grossinger Motors Arena
Flyover 2019 featuring Cardi B, 21 Savage, and many more
Sat 3:20 PM CDT · 31,958 guests
Providence Amphitheater
Bonner Springs, KS
Lil Baby
Fri 8 PM · 259 guests
MJN – Majed J. Nesheiwat Convention Center
Roots Picnic 2019
Sat 12 PM · 19,251 guests
The Mann Center for the Performing Arts
Gucci Mane & Lil Baby Live In Concert
Fri 8 PM · 9,474 guests
Albany Civic Center
splash! Festival 2019
Jul 11 – Jul 13 · 38,006 guests
Ferropolis
The Greatest Day Ever! Festival Presented By adidas Originals
Jul 13 – Jul 14 · 3,050 guests
Ford Amphitheater at Coney Island Boardwalk
Sun 3 PM · 314 guests
KUBE Summer Jam
Fri 7 PM PDT · 1,182 guests
106.1 KMEL Summer Jam 2019
Sun 7:30 PM PDT · 2,611 guests
Oracle Arena and Oakland Alameda County Coliseum
Thu 11 AM CDT · 27,112 guests
Kris Engelhart
Hatebreed Shakes The Foundations Of The Underground
April 30, 2019 feature story
Falling In Reverse bring Episode III to Charlotte, NC
May 2, 2019 feature story
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Jeff McBride: A Magickal Life
Imagine a magician who reaches into his hat to pull out the rabbit he previously hid there and finds himself not with a bunny but a unicorn. By the time Jeff McBride was a teenager he was appearing on national TV. Since then he has won world renown among lovers of magic and illusion. Whether gracing a stage in Las Vegas or Paris, performing a card trick under your nose, or teaching a master class to already accomplished conjurors, he is one of the contemporary masters of the arts of deception. He is also the follower of a spiritual path based on a form of magic that he says, far from being a deceit, is a path to sacred reality.
Purchase on DVD
Watch in USA with A GaiamTV Subscritption
Directed & Written by
Daniel Zuckerbrot
Producer/Executive Producer
Donna Zuckerbrot
Executive Producer, Vision TV
Alberta Nokes
Neville Ottey
Alan Gibb
Music Consultant
Patrick Russell
Title Design & Illustrations
Ken Nutt
Series Opening
Tango Media Group
Tony Crosse
Aaron Albert
Online Editor/Colourist
Dan Johnston
Jakob Thiesen
Ian Rodness
Kitchen Sync Digital Audio
Richard Hanet, Lewis Birnberg Hanet, LLP
Richard Warburton, Kay & Warburton
Jones Brown
Stock Footage/Archival Visuals
Robert Henrikson
The Miracle Factory
From Enter the Center
Composed and performed by Abigail McBride
From Beneath the Veil, Soles on Earth, Dancers of Twilight
Performed by Zingia
Composed by Katlyn & Michael Breene
Courtesy Sequoia Records
From Dreamspell
Composed and performed by Gary Stadler
Abigail McBride
Tobias Beckwith
Eugene Burger
Katlyn Breene
Michael Breene
Judith Bautista
Adam Brindley
Mark Buread
Jonathan Carp
Todd Carr
Marisa Carnesly
Allan Cleverley
Craig Conely
R. Heath Foxlee
Lee Grotte
Paul Kozak
Gerry Morrison
Jayson Morrison
Dan Quintana
Daniel Rolland
Jay Rosenberg
Mohamd Saleh
Finn Strandgaard
Kathryn Trevethan
Christine White
Jordan Wright
Jason Zommick
Vegas Vortex
Produced in association with VisionTV with the participation of the Canadian Film or Video Production Tax Credits and the Ontario film & Television Tax Credits.
MUM Magazine
Review by Barrie Richardson
Jeff is always a magician, always the enthusiastic entertainer. In any one day, he might produce a small rose for a desk clerk; vanish a coin borrowed from a person he meets in a check-out line and then discover the coin in a wrapped chocolate bar, and a little later, read the minds of a group of college girls sitting next to him in a coffee shop. That same night he might be headlining a show in Las Vegas where music, lights and costumes provide an ambiance for his mask-changing act and flawless sleight of hand. Then there is Jeff as the master teacher and organizer of the Magic and Mystery School, and Jeff as an initiator of the Burning Man Festival.
Jeff McBride- A Magickal Life was produced in Canada for a series on the lives of unusually creative persons. The DVD documents Jeff’s rise from a boy magician to a headliner in Las Vegas while still in his 20s and then his search for real magic and possibly more meaning to his life. The viewers follow Jeff on this odyssey We meet his friends in magic and in life, and we see how he develops concepts, rituals and philosophies that grow into novel and successful ventures.
We also learn how Jeff and his colleague, Eugene Burger developed a Magic & Mystery School that not only has courses for magicians, but also specialized programs for non-magicians, such as those who are in the health care professions and interested in the power of magic.
The viewer gets to see the drumming and dancing rituals of the Burning Man ceremony held each year in the desert, within which participants seem to have emotional and possibly spiritual experiences. Whether this is your cup of tea or not, the footage is fascinating and provocative.
I thoroughly like the insights we gained when we learn about some of Jeff’s early personality traits, as a cocky, aggressive and self-centered person who happily matures into an apparently considerate, even-tempered sage. Human flaws, missteps and idiosyncrasies make a report not only quite interesting , but also humanize the story.
If you want to get some fascinating insights in to the life of a unique and offbeat character who lives his life with enthusiasm and passion, kindness and respect for others, this is perfect for your library.
All in all I loved this documentary. Best of all for me was seeing short snippets of Jeff’s card manipulations, the mask act, his water bowls, and Miser’s Dream. It reminded me of how I felt when I first saw Harry Blackstone Sr. make a lighted light bulb first float in the air and then whoosh over our heads. This took my breath away. And so does the life, energy and art of Jeff McBride.
Jeff Stone
If you’re a fan of McBride, get it. If you’re not, get it. If you’ve never heard of McBride, get it. Get it? This DVD is a documentary style production with interviews of many of McBride’s friends, including Eugene Burger. There are a few sort of sections. In no particular order, you have interviews of friends, pivotal moments in McBride’s life, his spiritual/religious journey, and let’s call it words of wisdom from McBride.
If you are looking for a DVD with tricks, wrong alley. However, if you want to learn and see the progression of McBride’s career, right alley. I’ve always, personally enjoyed biographies of magicians. Genii Magazine (November 2007) had an excellent bio about Max Maven. I just eat that stuff up, so if you like bio’s you’re in luck.
My favorite parts were the “words of wisdom” from McBride. He just would say these things in some of the interview segments that would really resonate with me. Finally, my least favorite part, the part I could pretty much have totally done without was the footage of the fire dancing. Some of it was interesting and fascinating, and the interview segments where they discussed it were cool. But one can only stand so much footage of watching people dance in front of a fire.
I’m not here to mock Jeff’s beliefs or practices by any stretch. I feel that is one area that is off limits. Those are very sacred and special beliefs for Jeff and many times were part of the Pivotal moments in his life. I just felt that the footage was a bit too long for the average viewer. One other thing that would have been cool would be to see more about the Mystery School and more footage of Jeff performing.
Still, for a fun viewing that doesn’t require as much focus as a teaching video, yet still has the magic feel to it, this is the perfect Sunday night biography.
Magic Magazine
Review by Brad Henderson
Fans of Jeff McBride will consider this film, produced by award-winning Canadian documentarians Daniel & Donna Zuckerbrot, a must-have. Not only are small portions of some of McBride’s signature pieces archived, but his personal and performance philosophies are explored at length. Most importantly, it chronicles McBride as both a performer and a seeker of magic.
Those who are new to McBride may find this portrait distancing. While it accurately represents him and his worldview, the Zuckerbrots leap headfirst into McBride’s unique philosophy and spiritual practices that might push some viewer’s boundaries. He has immersed himself in a variety of disciplines which have helped create one the more unique acts in our field. More than that, this symbolic approach to magic is not only one of McBride’s secrets of artistic success but, whether used knowingly or not, a common element among other successful magical artists. As McBride says on symbolism in magic, “The audience may never be aware of that, and that’s the power of the magic.”
For some, this film will prove a fascinating insight into the creative process of one of magic’s most successful artists. Others may find it confusing or even off-putting. And some may prefer to avoid knowing altogether. After all, once the secret’s told, you may never look at the magic in the same way again.
Review by David Goodsell
Fifteen years ago Eugene Burger wrote that “the stunning visual images present in his work make [Jeff McBride] a true master of the bizarre.” In 1991, when this was written, Jeff had not yet fully developed his full-evening show. But even then he was influenced by “the sort of conjuring which…in Max Maven’s words, ‘references a larger magical universe beyond the boundaries of the performance’) can be found in other cultures and in other traditions.” We as spectators, and perhaps, for some, as more serious observers of trends in conjuring, recognize that there is something different about Jeff McBride. An initial reaction is that he is non-traditional. But, upon serious reflection we recognize that perhaps he is among the very few who are traditional magicians. Hmmm. Who is this person?
Now you have a chance to find out. His recent 50-minute DVD, JEFF McBRIDE – A MAGICKAL LIFE is a biographical “documentary [that] features Jeff in performance and takes you into his private world. A world where he and his partner Abigail focus on magickal events and rituals with powerful and ancient roots. Follow them from the bright lights of Vegas to Burning Man in Arizona and discover how magick is alive and present all around us.” You won’t learn any tricks, but you will learn about Jeff McBride.
Most of us have seen Jeff McBride perform. We have been impressed by his sleight-of-hand skills and by the drama, the theatricality, of his presentations. The costumes, the masks and the other props, fit Jeff. Few of us see ourselves doing magic the way he does it. But, you see, Jeff’s routines are much more than conjuring. They represent his “magickal life.” The mask is perhaps his best known trademark, and here we learn the origin of the concept as he presents it, how it grew out of the necessity of doing something… what… to capture audience attention in the rough and ready New York bars and dinner clubs which were his real training ground – a kind of combination of marshal arts and Japanese Kibuki theater. Masks – do we hide behind them? Do we purposefully use them? Do we need them? What lies behind them? Part of Jeff’s genius lies in his ability to sense how an audience will respond to ritual used in theatrical magic. I think Jeff would say that people respond without fully understanding why. They are entranced and amazed, and perhaps it is because the life lessons represented metaphorically in Jeff’s routines speak to some inner, subconscious understanding. Does that sound mystical? Maybe metaphysical? Yes, it does. Do I believe it is so? Maybe. I believe Jeff believes and that magic for him is wrapped in spirituality far more so than for most of us, and I respect that. For him the mask represented a transformation of the Trickster, where the tricks matter most, into the Sorcerer, where magic is power.
I think these transformations become evident as we watch this DVD; but I, for one, likely would not have recognized them had they not been explained here. Jeff describes his meteoric rise to success, to a headline spot in Las Vegas, and then the realization that there must be more. He is not the first to reach that point in life, what can be for some a turning point. Jeff sought the answer in a personal three-day vision quest in the solitude of the Nevada desert. For him real magic began at the fire. The results were, indeed, transforming, and drumming and fire dancing have been an important part of his life ever since. In addition, Jeff developed a strong desire to take the life-changing aspects of tribal drumming, rhythmic meditation and fire dancing into the theater. The sorcerer became the Oracle, and his magic changed in fundamental ways and ritual took on an even more important role. Jeff’s water bowls routine is a fine example of this. But the Oracle does more than perform. The Oracle becomes the teacher, as well, and it was in this stage that The Mystery School was founded in close association with Eugene Burger, who, Jeff will explain, has achieved the fourth and final point in his magical progress, that of Sage. The Mystery School, and later the Masters Classes, appear to be of equal importance to performance in Jeff’s life. Would that we all had attended The Mystery School!
The successful inclusion of ritual and ceremony in his shows and his teaching reflect the importance of the same in his continuing personal quest for spirituality. Magic is all about transformance, Jeff will tell you, and personal transformance is fundamental to happiness, emotional and physical health, mental achievement and spiritual growth. Dancing, drumming, the fire circle, with like-minded people seems something like a cleansing ritual. In fact, Jeff explains that the fire circle is composed of many circles, like the solar system. Those who dance close to the fire, in the orbit of Mercury, experience a more excited energy state than those further out. Each separate orbit provides its own benefit: graceful movement, rhythmic feeling, meditation, etc. Astrology? Perhaps. Alchemy? Here we learn that the fire circle is likened to the alchemist’s flask, where the base metals in our lives, holding us down, keeping us back, are melted down, the dross discarded, and in its place we can find silver and gold. These are interesting… no, intriguing… powerful concepts.
This is an excellent DVD, informative and entertaining. We are treated to Eugene Burger’s lovely Gypsy Thread routine and several segments from Jeff’s routines. We especially enjoyed the “Miser’s Dream” routine using a boy from the audience, and fully understood the tribal coming of age metaphor involved, once it was pointed out to us. We hear from Jeff’s wife, the lovely Abbi Spinner McBride, and Jeff’s long-time friend and manager, Tobias Beckwith, as well.
Storytelling magic? McBride’s magic is filled with stories. If you did not understand that before, you will after watching Jeff McBride – a Magical Life. And we predict you find much more than mere entertainment the next time you see him perform in person.
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Jim's Family
Rev. Jim Rehnberg and His Family
Jim lives in Algonquin, IL with his wife Marg and two little white dogs. Married 40+ years ago in Wheaton, IL, they have lived in Minnesota, Wisconsin, Michigan and are currently enjoying life by the Fox River.
They love Willow Creek Community Church, their neighborhood and enjoy meals out at Coopers Hawk, Bonefish Grill and Port Edward Restaurant.
If you would ever like to join Rehnberg's at church, please let them know. It's a wonderful place where people find deepened meaning and places to serve. (Saturdays @ 5:30 and Sundays @ 9 & 11:15am) Willow also provides live streaming @ www.willowcreek.tv during those times.
Lisa, Chad, Jim, Marg, Charissa, Dana
Jim and his wife Marg
Jim married Marg in 1975,
Art by Marg
BloxShop
Jim and Marg's five grandchildren in Tucson at a family reunion - 2016
Emma and Mini
These two girls fill our space with love.
Jim's daughter Charissa and her husband Dana Los Angeles, CA
Charissa
Charissa & Dana Nielsen
with 5 year old Cora
Los Angeles based session singer and composer, Charissa Nielsen, is versatile and experienced on stage and in the studio. Often called to engineer her own vocals, gather voices for a TV, Film, or Commercial project, or compose a song at a moment's notice, Charissa can deliver. Her vocals can be heard on a wide variety of national TV and RADIO commercials for Burger King, UPS, Tide, Cuties, Hanes, Old Navy, Jello, Nationwide Insurance, Comcast, X Box, Schick, and many more.
Dana Nielsen is a Los Angeles based, Grammy-nominated mixer, engineer, producer and saxophonist who has amassed credits that run the stylistic gamut from Neil Diamond to Slayer and just about every style in between.
Cora sings and dances with the best of them loves their new little dog Beau.
Jim's son Chad and his wife Lisa
Louisville, KY
Chad & Lisa
Team Expansion
Chad and Lisa with
their four children
Chad and Lisa have four children ages 8 through 15. and are missionaries with Team Expansion in the West End of Shawnee, Louisville, KY. Their motto is "“Transforming a Neighborhood, Transform the Nations.” The Lord moved them into the inner city in 2006. They experience His love every step of the way and believe they are called to serve their neighborhood, and while doing that, serve the nations.
Lisa's serves her family and community with a huge beautiful heart and blesses all with her love of music...and her new bass guitar. All four children are pianists and excel in school and other activities.
© 2006-2017 Professional Ministerial Services. All rights reserved.
"Rent-a-Rev" is a registered trademark of Professional Ministerial Services.
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Combination Therapy for Treating Hepatitis C Virus Infection
The present invention provides methods of treating hepatitis C virus (HCV) infection; methods of reducing the incidence of complications associated with HCV and cirrhosis of the liver; and methods of reducing viral load, or reducing the time to viral clearance, or reducing morbidity or mortality in the clinical outcomes, in patients suffering from HCV infection. The methods generally involve administering to the individual i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; and iii) an inhibitor of an HCV enzyme.
Blatt, Lawrence M. (San Francisco, CA)
A61K38/21; A61P31/14
20050208156 Plants extracts and the use thereof September, 2005 Ploch et al.
20090110675 USE OF PLATELET ACTIVATING FACTOR ACETYLHYDROLASE AS BIOMARKER FOR ANAPHYLAXIS April, 2009 Vadas
20050287032 Anti-bacterial protection to improve performance of post CMP clean brush December, 2005 Tregub et al.
20090155332 REPLACEMENT BONE TISSUE June, 2009 Sherry et al.
20090191138 NOVEL TOPICAL FORMULATIONS FOR IMPROVING THE APPEARANCE OF NAILS July, 2009 Dechow
20060067924 Probiotic bacteria and methods March, 2006 Lee et al.
20090238891 Method of producing a dry earthworm powder September, 2009 Ishii et al.
20090041808 Detection/Measurement Of Malaria Infection Disease Utilizing Natural Immunity By Hemozoin Induction, Screening Of Preventative Or Therapeutic Medicine For Malaria Infection Disease, And Regulation Of Natural Immunity Induction February, 2009 Akira et al.
20020131985 System for customizing personal care products September, 2002 Shana'a et al.
20070122395 Genetic and pharmacological regulation of antidepressant-sensitive biogenic amine transporters through PKG/p38 map kinase May, 2007 Blakely et al.
20050196460 Particulate cartilage compositions, processes for their preparation and methods for regenerating cartilage September, 2005 Malinin
LUCAS, ZACHARIAH
ARENT FOX LLP (1717 K Street, NW, WASHINGTON, DC, 20006-5344, US)
1. A method for treating a hepatitis C virus infection in an individual, the method comprising administering to the individual a IFN-α, at least one immunomodulatory agent, and at least one inhibitor of an HCV enzyme, in amounts effective to achieve a sustained viral response, wherein the immunomodulatory agent is one or more of IFN-γ, pirfenidone or a pirfenidone analog, a TNF antagonist, and thymosin-α.
2. The method of claim 1, wherein the inhibitor of an HCV enzyme is an HCV NS3 protease inhibitor.
3. The method of claim 1, wherein the inhibitor of an HCV enzyme is an HCV NS5B RNA-dependent RNA polymerase inhibitor.
4. The method of claim 1, comprising administering an HCV NS3 protease inhibitor and an HCV NS5B RNA-dependent RNA polymerase inhibitor.
5. The method of claim 1, wherein the immunomodulatory agent is IFN-γ administered subcutaneously in an amount of from about 10 μg to about 300 μg.
6. The method of claim 1, wherein the immunomodulatory agent is pirfenidone or a pirfenidone analog administered orally daily in an amount of from about 400 mg to about 3600 mg.
7. The method of claim 1, wherein the immunomodulatory agent is a TNF antagonist.
8. The method of claim 7, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, and adalimumab.
9. The method of claim 1, wherein the immunomodulatory agent is thymosin-α administered subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.
10. The method of any of claims 1-9, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
11. The method of claim 10, wherein the nucleoside analog is ribavirin.
12. The method of claim 10, wherein the nucleoside analog is levovirin.
13. The method of claim 10, wherein the nucleoside analog is viramidine.
14. The method of claim 10, wherein the nucleoside analog is isatoribine.
15. The method of claim 10, wherein the nucleoside analog is an L-nucleoside.
16. The method of claim 1, wherein the IFN-α is monoPEG (30 kD, linear)-ylated consensus IFN-α administered at a dosing interval of every 8 days to every 14 days.
17. The method of claim 1, wherein the IFN-α is monoPEG (30 1kD, linear)-ylated consensus IFN-α administered at a dosing interval of once every 7 days.
18. The method of any of claims 1-15, wherein the IFN-α is a pegylated IFN-α.
19. The method of claim 18, wherein the pegylated IFN-α is a pegylated IFN-α2 or a pegylated consensus IFN-α.
20. The method of claim 19, wherein the pegylated IFN-α is selected from the group consisting of peginterferon alfa-2a, peginterferon alfa-2b, and monoPEG (30 kD, linear)-ylated consensus IFN-α.
21. The method of claim 1, comprising administering effective amounts of IFN-γ and pirfenidone or a pirfenidone analog.
22. The method of claim 1, comprising administering effective amounts of IFN-γ and thymosin-α.
23. The method of claim 1, comprising administering effective amounts of IFN-γ and ribavirin.
24. The method of claim 1, comprising administering effective amounts of IFN-γ and levovirin.
25. The method of claim 1, comprising administering effective amounts of IFN-γ and viramidine.
26. The method of claim 1, comprising administering effective amounts of IFN-γ and an L-nucleoside.
27. The method of claim 1, comprising administering effective amounts of a TNF antagonist and IFN-γ.
28. The method of claim 27, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab and adalimumab.
29. The method of any of claims 21, 22, 27 or 28, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
34. The method of any of claims 21-33, wherein the IFN-α is a pegylated IFN-α.
36. The method of claim 34, wherein the pegylated IFN-α is selected from the group consisting of peginterferon alfa-2a, peginterferon alfa-2b and monoPEG (30 kD, linear)-ylated consensus IFN-α.
37. The method of any of claims 5-36, wherein the HCV enzyme inhibitor is an HCV NS3 protease inhibitor.
38. The method of any of claims 5-36, wherein the HCV enzyme inhibitor is an HCV NS5B RNA-dependent RNA polymerase inhibitor.
This invention is in the field of viral infection, particularly hepatitis C viral infection.
Hepatitis C virus (HCV) infection is the most common chronic blood borne infection in the United States. Although the numbers of new infections have declined, the burden of chronic infection is substantial, with Centers for Disease Control estimates of 3.9 million (1.8%) infected persons in the United States. Chronic liver disease is the tenth leading cause of death among adults in the United States, and accounts for approximately 25,000 deaths annually, or approximately 1% of all deaths. Studies indicate that 40% of chronic liver disease is HCV-related, resulting in an estimated 8,000-10,000 deaths each year. HCV-associated end-stage liver disease is the most frequent indication for liver transplantation among adults.
Antiviral therapy of chronic hepatitis C has evolved rapidly over the last decade, with significant improvements seen in the efficacy of treatment. Nevertheless, even with combination therapy using pegylated IFN-A plus ribavirin, 40% to 50% of patients fail therapy, i.e., are nonresponders or relapsers. These patients currently have no effective therapeutic alternative. In particular, patients who have advanced fibrosis or cirrhosis on liver biopsy are at significant risk of developing complications of advanced liver disease, including ascites, jaundice, variceal bleeding, encephalopathy, and progressive liver failure, as well as a markedly increased risk of hepatocellular carcinoma.
The high prevalence of chronic HCV infection has important public health implications for the future burden of chronic liver disease in the United States. Data derived from the National Health and Nutrition Examination Survey (NHANES III) indicate that a large increase in the rate of new HCV infections occurred from the late 1 960s to the early 1980s, particularly among persons between 20 to 40 years of age. It is estimated that the number of persons with long-standing HCV infection of 20 years or longer could more than quadruple from 1990 to 2015, from 750,000 to over 3 million. The proportional increase in persons infected for 30 or 40 years would be even greater. Since the risk of HCV-related chronic liver disease is related to the duration of infection, with the risk of cirrhosis progressively increasing for persons infected for longer than 20 years, this will result in a substantial increase in cirrhosis-related morbidity and mortality among patients infected between the years of 1965-1985.
HCV is an enveloped positive strand RNA virus in the Flaviviridae family. The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins of the virus. In the case of HCV, the generation of mature nonstructural proteins (NS2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first viral protease cleaves at the NS2-NS3 junction of the polyprotein. The second viral protease is serine protease contained within the N-terminal region of NS3 (herein referred to as “NS3 protease”). NS3 protease mediates all of the subsequent cleavage events at sites downstream relative to the position of NS3 in the polyprotein (i.e., sites located between the C-terminus of NS3 and the C-terminus of the polyprotein). NS3 protease exhibits activity both in cis, at the NS3-NS4 cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B sites. The NS4A protein is believed to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components.
Apparently, the formation of the complex between NS3 and NS4A is necessary for NS3-mediated processing events and enhances proteolytic efficiency at all sites recognized by NS3.
The NS3 protease also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B is an RNA-dependent RNA polymerase involved in the replication of HCV RNA.
There is a need in the art for improved methods for treating viral infections, e.g. hepatitis C viral infection. The present invention addresses this need.
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FEATURES OF THE INVENTION
The invention features a method of treating an HCV infection, generally involving administering to an individual (i) a Type I or a Type III interferon receptor agonist (ii) an immunomodulatory agent and (iii) an HCV enzyme inhibitor concurrently, in an amount effective to achieve a sustained viral response. In many embodiments, the Type I interferon receptor agonist is IFN-α. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRONαPEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In many embodiments, the immunomodulatory agent is selected from i) a Type II interferon receptor agonist; ii) a TNF antagonist; iii) pirfenidone or a pirfenidone analog; and iv) thymosin-α. In many embodiments, the subject method further provides administering to the individual an effective amount of a nucleoside analog, such as isatoribine, ribavirin, levovirin and viramidine.
In carrying out the methods of combination therapy for treating a hepatitis C viral infection in an individual as described above, (i) a Type I or Type III interferon receptor agonist (ii) an inmunomodulatory agent and (iii) an HCV enzyme inhibitor are administered to the individual. In some embodiments, two or more of the drugs are administered in the same formulation. In other embodiments, the Type I or III interferon receptor agonist, the immunomodulatory agent and the HCV enzyme inhibitor are administered in two or more separate formulations. When administered in separate formulations, a Type I or Type III interferon receptor agonist, an imununomodulatory agent, and an HCV enzyme inhibitor can be administered substantially simultaneously, or can be administered within about 24 hours of one another. In many embodiments, a Type I or Type III interferon receptor agonist, an immunomodulatory agent, and an HCV enzyme inhibitor are administered subcutaneously in multiple doses. Optionally, the Type I or Type III interferon receptor agonist, immunomodulatory agent, and/or HCV enzyme inhibitor is/are administered to the individual by a controlled drug delivery device. Optionally, the Type I or Type III interferon receptor agonist, immunomodulatory agent, and/or HCV enzyme inhibitor is/are administered to the individual substantially continuously or continuously by a controlled drug delivery device. Optionally, the controlled drug delivery device is an implantable infusion pump and the infusion pump delivers the Type I or Type III interferon receptor agonist, immunomodulatory agent, and/or HCV enzyme inhibitor to the individual by subcutaneous infusion.
In many embodiments, any of the above-described methods involve administering a Type I interferon receptor agonist that is a PEGylated IFN-α conjugate. In some embodiments, the PEGylated IFN-α conjugate is a monoPEGylated IFN-α. In other embodiments, the monoPEGylated IFN-α conjugate is an IFN-α polypeptide covalently linked to a single PEG moiety via a lysine residue or the N-terminal amino acid residue of the IFN-α polypeptide. In other embodiments, the monoPEGylated IFN-α conjugate is an IFN-α polypeptide covalently linked to a single PEG moiety via an amide bond between either the epsilon-amino group of a lysine residue or the alpha-amino group of the IFN-α polypeptide and an activated carboxyl group of the PEG moiety. In other embodiments, the monoPEGylated IFN-α conjugate is an IFN-α polypeptide covalently linked to a single, linear PEG moiety.
In other embodiments, the monoPEGylated IFN-α conjugate is an IFN-α polypeptide covalently linked to a single, linear 30 kD PEG moiety (“monoPEG(30 kD, linear)-ylated IFN-α”). In other embodiments, the monoPEGylated IFN-α conjugate is an IFN-α polypeptide covalently linked to a single, linear 30 kD PEG moiety via an amide bond between the epsilon-amino group of a lysine residue or the alpha-amino group of the IFN-α polypeptide and an activated carboxyl group of the PEG moiety. In other embodiments, the monoPEGylated IFN-α conjugate is an IFN-α polypeptide covalently linked to a single, linear 30 kD PEG via an amide bond between the epsilon-amino group of a lysine residue or the alpha-amino group of the IFN-α polypeptide and an activated propionyl group of the PEG moiety. In other embodiments, the monoPEGylated IFN-α conjugate is an IFN-α polypeptide covalently linked to a single, linear monomethoxy-PEG (mPEG). In other embodiments, the monoPEGylated IFN-α conjugate is the product of a condensation reaction between an IFN-α polypeptide and a linear, succinimidyl propionate ester-activated 30 kD mPEG. In any of the foregoing methods using a PEGylated IFN-α conjugate, the IFN-α polypeptide can be a consensus interferon (CIFN) polypeptide. In any of the foregoing methods using a PEGylated IFN-α conjugate, the IFN-α polypeptide can be a CIFN polypeptide that is interferon alfacon-1.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, IFN-γ, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, IFN-γ, ribavirin, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, IFN-γ, pirfenidone or a pirfenidone analog, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, pirfenidone or a pirfenidone analog, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, ribavirin, pirfenidone or a pirfenidone analog, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, an L-nucleoside, pirfenidone or a pirfenidone analog, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, IFN-γ, a TNF antagonist, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor. In some embodiments, the TNF antagonist is selected from HUMIRA, ENBREL, and REMICADE.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, a TNF antagonist, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor. In some embodiments, the TNF antagonist is selected from HUMIRA, ENBREL, and REMICADE.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, ribavirin, a TNF antagonist, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor. In some embodiments, the TNF antagonist is selected from HUMIRA, ENBREL, and REMICADE.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, an L-nucleoside, a TNF antagonist, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor. In some embodiments, the TNF antagonist is selected from HUMIRA, ENBREL, and REMICADE.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, IFN-γ, an L-nucleoside, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, IFN-γ, thymosin-α, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, thymosin-α, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, ribavirin, thymosin-α, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α In some embodiments, the IFN-α is monoPEG(30 1kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, an L-nucleoside, thymosin-α, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, IFN-γ, levovirin, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, IFN-γ, viramidine, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
In one aspect, the present invention provides a combination therapy for treating an HCV infection in an individual, the method comprising administering IFN-α, IFN-γ, isatoribine, and an HCV enzyme inhibitor in combined effective amounts to achieve a sustained viral response. In some embodiments, the IFN-α is INFERGEN® consensus IFN-α. In some embodiments, the IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the IFN-α is PEG-INTRON®PEGylated IFN-α2b. In some embodiments, the IFN-α is PEGASYS®PEGylated IFN-α2a. In some embodiments, the HCV enzyme inhibitor is an NS3 protease inhibitor. In other embodiments, the HCV enzyme inhibitor is an NS5B RNA-dependent RNA polymerase inhibitor.
As used herein, the terms “treatment,” “treating,” and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease. “Treatment,” as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that may be associated with or caused by a primary disease (as in liver fibrosis that can result in the context of chronic HCV infection); (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.
The terms “individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to a mammal, including, but not limited to, primates, including simians and humans.
The term “treatment failure patients” (or “treatment failures”) as used herein generally refers to HCV-infected patients who failed to respond to previous therapy for HCV (referred to as “non-responders”) or who initially responded to previous therapy, but in whom the therapeutic response was not maintained (referred to as “relapsers”). The previous therapy generally can include treatment with IFN-α monotherapy or IFN-α combination therapy, where the combination therapy may include administration of IFN-α and an antiviral agent such as ribavirin.
The term “pharmacokinetic profile,” as used herein, refers to the profile of the curve defined by a patient's serum concentration of PEGylated IFN-α as a function of time, following the administration of PEGylated IFN-α to the patient. “Area under the curve,” or “AUC,” refers to the integrated area under the curve defined by a patient's serum concentration of PEGylated IFN-α as a function of time, following the administration of PEGylated IFN-α to the patient.
As used herein, the term “a Type I interferon receptor agonist” refers to any naturally occurring or non-naturally occurring ligand of human Type I interferon receptor, which binds to and causes signal transduction via the receptor. Type I interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.
As used herein, the term “a Type III interferon receptor agonist” refers to any naturally occurring or non-naturally occurring ligand of human IL-28 receptor a (“IL-28R”), the amino acid sequence of which is described by Sheppard, et al., infra., that binds to and causes signal transduction via the receptor.
As used herein, the terms “immunomodulator” and “immunomodulatory agent” refer to any agent, other than (i) a Type I or Type III interferon receptor agonist and (ii) a nucleoside, that stimulates immune cell mediated destruction of virus-infected cells. The term “immunomodulatory agent” includes, but is not limited to, Type II interferon receptor agonists (including IFN-γ); TNF antagonists; pirfenidone and pirfenidone analogs; and thymosin-α (Zadaxin®; SciClone Pharmaceuticals); and the like.
As used herein, the term “nucleoside” refers to a compound composed of any pentose or modified pentose moiety attached to a specific position of a heterocycle or to the natural position of a purine (9-position) or pyrimidine (1-position) or to the equivalent position in an analog.
As used herein, the term “nucleotide” refers to a phosphate ester substituted on the 5′-position of a nucleoside.
As used herein, the term “heterocycle” refers to a monovalent saturated or unsaturated carbocyclic radical having at least one hetero atom, such as N, O, S, Se or P, within the ring, each available position of which can be optionally substituted, independently, with, e.g., hydroxyl, oxo, amino, imino, lower alkyl, bromo, chloro and/or cyano. Included within the term “heterocycle” are purines and pyrimidines.
As used herein, the term “purine” refers to nitrogenous bicyclic heterocycles.
As used herein, the term “pyrimidine” refers to nitrogenous monocyclic heterocycles.
As used herein, the term “L-nucleoside” refers to a nucleoside compound that has an L-ribose sugar moiety.
As used herein, the term “pirfenidone” refers to 5-methyl-1-phenyl-2-(1H)-pyridone. As used herein, the term “pirfenidone analog” refers to any compound of Formula I, IIA or IIB below. A “specific pirfenidone analog,” and all grammatical variants thereof, refers to, and is limited to, each and every pirfenidone analog shown in Table 1.
As used herein, the term “a Type II interferon receptor agonist” refers to any naturally-occurring or non-naturally-occurring ligand of a human Type II interferon receptor which binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.
As used herein, the term “HCV enzyme inhibitor” refers to any agent that inhibits an enzymatic activity of an enzyme encoded by HCV. The term “HCV enzyme inhibitor” includes, but is not limited to, agents that inhibit HCV NS3 protease activity; agents that inhibit HCV NS3 helicase activity; and agents that inhibit HCV NS5B RNA-dependent RNA polymerase activity.
As used herein, the terms “HCV NS3 protease inhibitor” and “NS3 protease inhibitor” refer to any agent that inhibits the protease activity of HCV NS3/NS4A complex.
The term “hepatitis virus infection” refers to infection with one or more of hepatitis A, B, C, D, or E virus, with blood-borne hepatitis viral infection being of particular interest, particularly hepatitis C virus infection.
The term “sustained viral response” (SVR; also referred to as a “sustained response” or a “durable response”), as used herein, refers to the response of an individual to a treatment regimen for HCV infection, in terms of serum HCV titer. Generally, a “sustained viral response” refers to no detectable HCV RNA (e.g., less than about 500, less than about 200, or less than about 100 genome copies per milliliter serum) found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of treatment.
As used herein, the term “hepatic fibrosis,” used interchangeably herein with “liver fibrosis,” refers to the growth of scar tissue in the liver that can occur in the context of a chronic hepatitis infection.
As used herein, the term “liver function” refers to a normal function of the liver, including, but not limited to, a synthetic function, including, but not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5′-nucleosidase, γ-glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.
The term “dosing event” as used herein refers to administration of an antiviral agent to a patient in need thereof, which event may encompass one or more releases of an antiviral agent from a drug dispensing device. Thus, the term “dosing event,” as used herein, includes, but is not limited to, installation of a continuous delivery device (e.g., a pump or other controlled release injectible system); and a single subcutaneous injection followed by installation of a continuous delivery system.
“Continuous delivery” as used herein (e.g., in the context of “continuous delivery of a substance to a tissue”) is meant to refer to movement of drug to a delivery site, e.g., into a tissue in a fashion that provides for delivery of a desired amount of substance into the tissue over a selected period of time, where about the same quantity of drug is received by the patient each minute during the selected period of time.
“Controlled release” as used herein (e.g., in the context of “controlled drug release”) is meant to encompass release of substance (e.g., a Type I or Type III interferon receptor agonist, e.g., IFN-α) at a selected or otherwise controllable rate, interval, and/or amount, which is not substantially influenced by the environment of use. “Controlled release” thus encompasses, but is not necessarily limited to, substantially continuous delivery, and patterned delivery (e.g., intermittent delivery over a period of time that is interrupted by regular or irregular time intervals).
“Patterned” or “temporal” as used in the context of drug delivery is meant delivery of drug in a pattern, generally a substantially regular pattern, over a pre-selected period of time (e.g., other than a period associated with, for example a bolus injection). “Patterned” or “temporal” drug delivery is meant to encompass delivery of drug at an increasing, decreasing, substantially constant, or pulsatile, rate or range of rates (e.g., amount of drug per unlit time, or volume of drug formulation for a unit time), and further encompasses delivery that is continuous or substantially continuous, or chronic.
The term “controlled drug delivery device” is meant to encompass any device wherein the release (e.g., rate, timing of release) of a drug or other desired substance contained therein is controlled by or determined by the device itself and not substantially influenced by the environment of use, or releasing at a rate that is reproducible within the environment of use.
By “substantially continuous” as used in, for example, the context of “substantially continuous infusion” or “substantially continuous delivery” is meant to refer to delivery of drug in a maimer that is substantially uninterrupted for a pre-selected period of drug delivery, where the quantity of drug received by the patient during any 8 hour interval in the pre-selected period never falls to zero. Furthermore, “substantially continuous” drug delivery can also encompass delivery of drug at a substantially constant, pre-selected rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time) that is substantially uninterrupted for a pre-selected period of drug delivery.
By “substantially steady state” as used in the context of a biological parameter that may vary as a function of time, it is meant that the biological parameter exhibits a substantially constant value over a time course, such that the area under the curve defined by the value of the biological parameter as a function of time for any 8 hour period during the time course (AUC8hr) is no more than about 20% above or about 20% below, and preferably no more than about 15% above or about 15% below, and more preferably no more than about 10% above or about 10% below, the average area under the curve of the biological parameter over an 8 hour period during the time course (AUC8hr average). The AUC8hr average is defined as the quotient (q) of the area under the curve of the biological parameter over the entirety of the time course (AUCtotal) divided by the number of 8 hour intervals in the time course (ttotal1/3days), i.e., q=(AUCtotal)/(ttotal1/3days). For example, in the context of a serum concentration of a drug, the serum concentration of the drug is maintained at a substantially steady state during a time course when the area under the curve of serum concentration of the drug over time for any 8 hour period during the time course (AUC8hr) is no more than about 20% above or about 20% below the average area under the curve of serum concentration of the drug over an 8 hour period in the time course (AUC8hr average), i.e., the AUC8hr is no more than 20% above or 20% below the AUC8hr average for the serum concentration of the drug over the time course.
As used herein, any compound or agent described as “effective for the avoidance or amelioration of side effects induced by a Type I interferon receptor agonist,” or as “effective for reducing or eliminating the severity or occurrence of side effects induced by a Type I interferon receptor agonist,” or any compound or agent described by language with a meaning similar or equivalent to that of either of the foregoing quoted passages, is/are defined as a compound(s) or agent(s) that when co-administered to a patient in an effective amount along with a given dosing regimen of a subject Type I interferon receptor agonist combination therapy, abates or eliminates the severity or occurrence of side effects experienced by a patient in response to the given dosing regimen of the a Type I interferon receptor agonist combination therapy, as compared to the severity or occurrence of side effects that would have been experienced by the patient in response to the same dosing regimen of the a Type I interferon receptor agonist combination therapy without co-administration of the agent.
In many embodiments, the effective amounts of a Type I interferon receptor agonist and a second therapeutic agent are synergistic amounts. As used herein, a “synergistic combination” or a “synergistic amount” of a Type I interferon receptor agonist and a second therapeutic agent is a combination or amount that is more effective in the therapeutic or prophylactic treatment of a disease than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the Type I interferon receptor agonist when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the second therapeutic agent when administered at the same dosage as a monotherapy.
Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a Type I interferon receptor agonist” includes a plurality of such agonists and reference to “the NS3 inhibitor” includes reference to one or more NS3 inhibitors and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
Without intending a limitation to any particular mechanism, the present invention arises in part from the discernment of an adverse effect that the inhibition of NS3 will have on cytotoxic T lymphocyte (CTL)-mediated clearance of virally infected tissue. The adverse effect on CTL activity is believed to originate from the pleiotropic effects of Type I interferon receptor activation, which include the induction of TNF (and other inflammatory cytokines). Interferon response factor 3 (IRF3) mediates the transduction of signal from activated Type I interferon receptor. NS3 mediates HCV resistance to Type I interferon therapy by blocking the activation and effector function of IRF3 (Foy, et al., Science 300: 1145-1148 (2003)). Thus, the inhibition of NS3 will improve IRF3 -mediated signal transduction, leading to stronger TNF induction. The increase in TNF will create a cytokine pattern that disfavors TH1 activation, thereby reducing CTL-mediated clearance of virally infected tissue. The regimens of the present invention include an immunomodulator to moderate or offset the NS3 inhibitor's negative impact on CTL activity in HCV infection.
In addition, the above-described mechanism applies to intervention with an inhibitor of HCV NS5B RNA-dependent RNA polymerase (RDRP). Since RDRP activity is needed for replication of viral RNA template encoding NS3, the inhibition of RDRP activity will downregulate NS3 expression and improve IRF3-mediated induction of TNF. Thus, the immunomodulator in the present regimens will moderate or offset the RDRP inhibitor's negative impact on CTL activity in HCV infection.
The present invention provides methods of treating an HCV infection; and methods of treating complications or sequelae of an HCV infection, e.g., liver fibrosis. The methods generally involve a combination therapeutic regimen, wherein a Type I or a Type III interferon receptor agonist, one or more immunomodulatory agents, and one or more HCV enzyme inhibitors are administered to an individual in need thereof.
Hepatitis Virus Infections
The present invention provides methods for treating a hepatitis C virus (HCV) infection. The methods generally involve a combination therapy comprising administering to an individual in need thereof combined effective amounts of i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; and iii) an inhibitor of an HCV enzyme, where the combination therapy is effective to decrease viral load in the individual, and to achieve a sustained viral response. Optionally, the subject method further provides administering to the individual an effective amount of a nucleoside analog, such as ribavirin, levovirin, and viramidine. Of particular interest in many embodiments is treatment of humans. In many embodiments, the Type I interferon receptor agonist is IFN-α.
Whether a subject method is effective in treating an HCV infection can be determined by measuring viral load, or by measuring a parameter associated with HCV infection, including, but not limited to, liver fibrosis, elevations in serum transaminase levels, and necroinflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail below.
Viral load can be measured by measuring the titer or level of virus in serum. These methods include, but are not limited to, a quantitative polymerase chain reaction (PCR) and a branched DNA (bDNA) test. Quantitative assays for measuring the viral load (titer) of HCV RNA have been developed. Many such assays are available commercially, including a quantitative reverse transcription PCR (RT-PCR) (Amplicor HCV Monitor™, Roche Molecular Systems, New Jersey); and a branched DNA (deoxyribonucleic acid) signal amplification assay (Quantiplex™ HCV RNA Assay (bDNA), Chiron Corp., Emeryville, Calif. See, e.g., Gretch et al. (1995) Ann. Intern. Med. 123:321-329.
In general, an effective amount of a therapeutic agent that is administered as part of a subject combination therapy is an amount that is effective to reduce viral load to undetectable levels, e.g., to less than about 5000, less than about 1000, less than about 500, or less than about 200 genome copies/mL serum. In some embodiments, an effective amount of a therapeutic agent that is administered as part of a subject combination therapy is an amount that is effective to reduce viral load to less than 100 genome copies/mL serum. In many embodiments, the methods of the invention achieve a sustained viral response, e.g., the viral load is reduced to undetectable levels for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of treatment.
As noted above, whether a subject method is effective in treating an HCV infection can be determined by measuring a parameter associated with HCV infection, such as liver fibrosis. Methods of determining the extent of liver fibrosis are discussed in detail below. In some embodiments, the level of a serum marker of liver fibrosis indicates the degree of liver fibrosis.
As one non-limiting example, levels of serum alanine aminotransferase (ALT) are measured, using standard assays. In general, an ALT level of less than about 45 international units is considered normal. In some embodiments, an effective amount of a therapeutic agent that is administered as part of a subject combination therapy is an amount effective to reduce ALT levels to less than about 45 U/ml serum.
A therapeutically effective amount of a therapeutic agent that is administered as part of a subject combination therapy is an amount that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or to a placebo-treated individual. Methods of measuring serum markers include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.
Liver Fibrosis
Liver fibrosis is a precursor to the complications associated with liver cirrhosis, such as portal hypertension, progressive liver insufficiency, and hepatocellular carcinoma. A reduction in liver fibrosis thus reduces the incidence of such complications. Accordingly, the present invention further provides methods of reducing the likelihood that an individual will develop complications associated with cirrhosis of the liver.
The present methods generally involve administering therapeutically effective amounts of i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; and iii) an inhibitor of an HCV enzyme. As used herein, “effective amounts” of therapeutic agents that are administered in a subject combination therapy are any combined dosage that is effective in reducing liver fibrosis or reduce the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.
The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an imununomodulatory agent; and iii) an inhibitor of an HCV enzyme that are effective for prophylaxis or therapy of liver fibrosis in the individual, e.g., increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.
Whether treatment with a combination of i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; and iii) an inhibitor of an HCV enzyme is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by “grade” as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by “stage” as being reflective of long-term disease progression. See, e.g., Brunt (2000) Hepatol. 31:241-246; and METAVIR (1994) Hepatology 20:15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.
The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.
Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage. Knodell (1981) Hepatol. 1:431.
In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J. Hepatol. 13:372.
The Ishak scoring system is described in Ishak (1995) J. Hepatol. 22:696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.
The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.
In some embodiments, therapeutically effective amounts of a Type I or III interferon receptor agonist, an immunomodulatory agent, and an HCV enzyme inhibitor are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre- and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a Type I or III interferon receptor agonist, an immunomodulatory agent, and an HCV enzyme inhibitor reduce liver fibrosis by at least one unit in the METAVIR, the Inodell, the Scheuer, the Ludwig, or the Ishalc scoring system.
Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with a subject combination therapy. Morphometric computerized semi-automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.
In another embodiment, effective amounts of i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; and iii) an inhibitor of an HCV enzyme are any combined dosage that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.
Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include α-2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.
In another embodiment, therapeutically effective amounts of i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; and iii) an inhibitor of an HCV enzyme are any combined dosage that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e.g., enzyme-linled immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.
Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with dual IFN receptor agonist therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.
As used herein, a “complication associated with cirrhosis of the liver” refers to a disorder that is a sequelae of decompensated liver disease, i.e., or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.
In another embodiment, therapeutically effective amounts of i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; and iii) an inhibitor of an HCV enzyme are any combined dosage that is effective in reducing the incidence of (e.g., the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.
Whether combination therapy with a Type I or III interferon receptor agonist, an immunomodulatory agent and an HCV enzyme inhibitor is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.
Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering therapeutically effective amounts of i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; and iii) an inhibitor of an HCV enzyme. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5′-nucleosidase, γ-glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.
Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.
Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins. The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays. Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.
In another embodiment, therapeutically effective amounts of i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; and iii) an inhibitor of an HCV enzyme are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 3 0%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. In one non-limiting example, therapeutically effective amounts of i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; and iii) an inhibitor of an HCV enzyme are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to withhiin a normal range. In another non-limiting example, therapeutically effective amounts of i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; and iii) an inhibitor of an HCV enzyme any combined dosage effective to increase a reduced level of a serum marker of liver ftmction by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.
Type I Interferon Receptor Agonists
In any of the above-described methods, in some embodiments a Type I interferon receptor agonist is administered. Type I interferon receptor agonists include an IFN-α; an IFN-β an IFN-tau; an IFN-ω; antibody agonists specific for a Type I interferon receptor; and any other agonist of Type I interferon receptor, including non-polypeptide agonists.
Interferon-Alpha
Any known IFN-α can be used in the instant invention. The term “interferon-alpha” as used herein refers to a family of related polypeptides that inhibit viral replication and cellular proliferation and modulate immune response. The term “IFN-α” includes naturally occurring IFN-α; synthetic IFN-α; derivatized IFN-α (e.g., PEGylated IFN-α, glycosylated IFN-α, and the like); and analogs of naturally occurring or synthetic IFN-α; essentially any IFN-α that has antiviral properties, as described for naturally occurring IFN-α.
Suitable alpha interferons include, but are not limited to, naturally-occurring IFN-α (including, but not limited to, naturally occurring IFN-α2a, IFN-α2b); recombinant interferon alpha-2b such as Intron-A interferon available from Schering Corporation, Kenilworth, N.J.; recombinant interferon alpha-2a such as Roferon interferon available from Hoffmann-La Roche, Nutley, N.J.; recombinant interferon alpha-2C such as Berofor alpha 2 interferon available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.; interferon alpha-n1, a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan or as Weliferon interferon alpha-n1 (INS) available from the Glaxo-Wellcome Ltd., London, Great Britain; and interferon alpha-n3 a mixture of natural alpha interferons made by Interferon Sciences and available from the Purdue Frederick Co., Norwalk, Conn., under the Alferon Tradename.
The term “IFN-α” also encompasses consensus IFN-α. Consensus IFN-α (also referred to as “CIFN” and “IFN-con” and “consensus interferon”) encompasses but is not limited to the amino acid sequences designated IFN-con1, IFN-con2 and IFN-con3 which are disclosed in U.S. Pat. Nos. 4,695,623 and 4,897,471; and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (e.g., INFERGEN®), InterMune, Inc., Brisbane, Calif.). IFN-con1 is the consensus interferon agent in the INFERGEN® alfacon-1 product. The INFERGEN® consensus interferon product is referred to herein by its brand name (INFERGEN®) or by its generic name (interferon alfacon-1). DNA sequences encoding IFN-con may be synthesized as described in the aforementioned patents or other standard methods. Use of CIFN is of particular interest.
Also suitable for use in the present invention are fusion polypeptides comprising an IFN-α and a heterologous polypeptide. Suitable IFN-α fusion polypeptides include, but are not limited to, Albuferon-alpha™ (a fusion product of human albumin and IFN-α; Human Genome Sciences; see, e.g., Osborn et al. (2002) J. Pharmacol. Exp. Therap. 303:540-548). Also suitable for use in the present invention are gene-shuffled forms of IFN-α. See., e.g., Masci et al. (2003) Curr. Oncol. Rep. 5:108-113.
PEGylated Interferon-Alpha
The term “IFN-α” also encompasses derivatives of IFN-α that are derivatized (e.g., are chemically modified) to alter certain properties such as serum half-life. As such, the term “IFN-α” includes glycosylated IFN-α; IFN-α derivatized with polyethylene glycol (“PEGylated IFN-α”); and the like. PEGylated IFN-α, and methods for making same, is discussed in, e.g., U.S. Pat. Nos. 5,382,657; 5,981,709; and 5,951,974. PEGylated IFN-α encompasses conjugates of PEG and any of the above-described IFN-α molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman La-Roche, Nutley, N.J.), interferon alpha 2b (Intron, Schering-Plough, Madison, N.J.), interferon alpha-2c (Berofor Alpha, Boebringer Ingelheim, Ingelheim, Germany); and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (INFERGEN(®, InterMune, Inc., Brisbane, Calif.).
Any of the above-mentioned IFN-α polypeptides can be modified with one or more polyethylene glycol moieties, i.e., PEGylated. The PEG molecule of a PEGylated IFN-α polypeptide is conjugated to one or more amino acid side chains of the IFN-α polypeptide. In some embodiments, the PEGylated IFN-α contains a PEG moiety on only one amino acid. In other embodiments, the PEGylated IFN-α contains a PEG moiety on two or more amino acids, e.g., the IFN-α contains a PEG moiety attached to two, three, four, five, six, seven, eight, nine, or ten different amino acid residues.
IFN-α may be coupled directly to PEG (i.e., without a linking group) through an amino group, a sulfhydryl group, a hydroxyl group, or a carboxyl group.
In some embodiments, the PEGylated IFN-α is PEGylated at or near the amino terminus (N-terminus) of the IFN-α polypeptide, e.g., the PEG moiety is conjugated to the IFN-α polypeptide at one or more amino acid residues from amino acid 1 through amino acid 4, or from amino acid 5 through about 10.
In other embodiments, the PEGylated IFN-α is PEGylated at one or more amino acid residues from about 10 to about 28.
In other embodiments, the PEGylated IFN-α is PEGylated at or near the carboxyl terminus (C-terminus) of the IFN-α polypeptide, e.g., at one or more residues from amino acids 156-166, or from amino acids 150 to 155.
In other embodiments, the PEGylated IFN-α is PEGylated at one or more amino acid residues at one or more residues from amino acids 100-114.
The polyethylene glycol derivatization of amino acid residues at or near the receptor-binding and/or active site domains of the IFN-α protein can disrupt the functioning of these domains. In certain embodiments of the invention, amino acids at which PEGylation is to be avoided include amino acid residues from amino acid 30 to amino acid 40; and amino acid residues from amino acid 113 to amino acid 149.
In some embodiments, PEG is attached to IFN-α via a linking group. The linking group is any biocompatible linking group, where “biocompatible” indicates that the compound or group is non-toxic and may be utilized in vitro or in vivo without causing injury, sickness, disease, or death. PEG can be bonded to the linking group, for example, via an ether bond, an ester bond, a thiol bond or an amide bond. Suitable biocompatible linking groups include, but are not limited to, an ester group, an amide group, an imide group, a carbamate group, a carboxyl group, a hydroxyl group, a carbohydrate, a succinimide group (including, for example, succinimidyl succinate (SS), succinimidyl propionate (SPA), succinimidyl butanoate (SBA), succinimidyl carboxymethylate (SCM), succinimidyl succinamide (SSA) or N-hydroxy succinimide (NHS)), an epoxide group, an oxycarbonylimidazole group (including, for example, carbonyldimidazole (CDI)), a nitro phenyl group (including, for example, nitrophenyl carbonate (NPC) or trichlorophenyl carbonate (TPC)), a trysylate group, an aldehyde group, an isocyanate group, a vinylsulfone group, a tyrosine group, a cysteihe group, a histidine group or a primary amine.
Methods for making succinimidyl propionate (SPA) and succinimidyl butanoate (SBA) ester-activated PEGs are described in U.S. Pat. No. 5,672,662 (Harris, et al.) and WO 97/03106.
Methods for attaching a PEG to an IFN-α polypeptide are known in the art, and any known method can be used. See, for example, by Park et al, Anticancer Res., 1:373-376 (1981); Zaplipsky and Lee, Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications, J. M. Harris, ed., Plenum Press, NY, Chapter 21 (1992); U.S. Pat. No. 5,985,265; U.S. Pat. No. 5,672,662 (Harris, et al.) and WO 97/03106.
Pegylated IFN-α, and methods for making same, is discussed in, e.g., U.S. Pat. Nos. 5,382,657; 5,981,709; 5,985,265; and 5,951,974. Pegylated IFN-α encompasses conjugates of PEG and any of the above-described IFN-α molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman LaRoche, Nutley, N.J.), where PEGylated Roferon is known as Pegasys (Hoffman LaRoche); interferon alpha 2b (Intron, Schering-Plough, Madison, N.J.), where PEGylated Intron is known as PEG-Intron (Schering-Plough); interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon (CIFN) as defined by determination of a consensus sequence of naturally occurring interferon alphas (INFERGEN®, InterMune, Inc., Brisbane, Calif.), where PEGylated CIFN is referred to as PEG-CIFN.
In many embodiments, the PEG is a monomethoxyPEG molecule that reacts with primary amine groups on the IFN-α polypeptide. Methods of modifying polypeptides with monomethoxy PEG via reductive alkylation are known in the art. See, e.g., Chamow et al. (1994) Bioconj. Chem. 5:133-140.
In one non-limiting example, PEG is linked to IFN-α via an SPA linking group. SPA esters of PEG, and methods for making same, are described in U.S. Pat. No. 5,672,662. SPA linkages provide for linkage to free amine groups on the IFN-α polypeptide.
For example, a PEG molecule is covalently attached via a linkage that comprises an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the IFN-α polypeptide. Such a bond can be formed, e.g., by condensation of an α-methoxy, omega propanoic acid activated ester of PEG (mPEGspa).
In some embodiments, the invention employs a PEG-modified CIFN, where the PEG moiety is attached to a lysine residue chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165. In these embodiments, the PEG moiety can be a linear PEG moiety having an average molecular weight of about 30 kD.
In other embodiments, the invention employs a PEG-modified CIFN, where the PEG moiety is attached to a lysine residue chosen from lys121, lys134, lys135, and lys165. In these embodiments, the PEG moiety can be a linear PEG moiety having an average molecular weight of about 30 kD.
As one non-limiting example, one monopegylated CIFN conjugate preferred for use herein has a linear PEG moiety of about 30 kD attached via a covalent linkage to the CIFN polypeptide, where the covalent linkage is an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the CIFN polypeptide, where the surface-exposed lysine residue is chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165, and the amide bond is formed by condensation α-methoxy, omega propanoic acid activated ester of PEG.
Linking Groups
In some embodiments, PEG is attached to IFN-α via a linking group. The linking group is any biocompatible linking group, where “biocompatible” indicates that the compound or group is essentially non-toxic and may be utilized in vivo without causing a significant adverse response in the subject, e.g., injury, sickness, disease, undesirable immune response, or death. PEG can be bonded to the linking group, for example, via an ether bond, an ester bond, a thio ether bond or an amide bond. Suitable biocompatible linking groups include, but are not limited to, an ester group, an amide group, an imide group, a carbamate group, a carboxyl group, a hydroxyl group, a carbohydrate, a succinimide group (including, for example, succinimidyl succinate (SS), succinimidyl propionate (SPA), succinimidyl butanoic acid (SBA), succinimidyl carboxymethylate (SCM), succinimidyl succinamide (SSA) or N-hydroxy succinimide (NHS)), an epoxide group, an oxycarbonylimidazole group (including, for example, carbonyldimidazole (CDI)), a nitro phenyl group (including, for example, nitrophenyl carbonate (NPC) or trichlorophenyl carbonate (TPC)), a trysylate group, an aldehyde group, an isocyanate group, a vinylsulfone group, a tyrosine group, a cysteine group, a histidine group or a primary amine.
In many embodiments, the PEG is a monomethoxyPEG molecule that reacts with primary amine groups on the IFN-α polypeptide. Methods of modifying polypeptides with monomethoxy PEG via reductive allcylation are known in the art. See, e.g., Chamow et al. (1994) Bioconj. Chem. 5:133-140.
For example, a PEG molecule is covalently attached via a linkage that comprises an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the IFN-α polypeptide. Such a bond can be formed, e.g., by condensation of an a-methoxy, omega propanoic acid activated ester of PEG (mPEGspa).
As one non-limiting example, monopegylated CIFN has a linear PEG moiety of about 30 kD attached via a covalent linkage to the CIFN polypeptide, where the covalent linkage is an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the CIFN polypeptide, where the surface-exposed lysine residue is chosen from lys121, lys134, lys135, and lys165, and the amide bond is formed by condensation of an a-methoxy, omega propanoic acid activated ester of PEG.
Methods for attaching a PEG molecule to an IFN-α polypeptide are known in the art, and any known method can be used. See, for example, by Park et al, Anticancer Res., 1:373-376 (1981); Zaplipsky and Lee, Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications, J. M. Harris, ed., Plenwn Press, NY, Chapter 21 (1992); and U.S. Pat. No. 5,985,265.
Polyethylene glycol suitable for conjugation to an IFN-α polypeptide is soluble in water at room temperature, and has the general formula R(O—CH2—CH2)nO—R, where R is hydrogen or a protective group such as an alkyl or an alkanol group, and where n is an integer from 1 to 1000. Where R is a protective group, it generally has from 1 to 8 carbons.
In many embodiments, PEG has at least one hydroxyl group, e.g., a terminal hydroxyl group, which hydroxyl group is modified-to generate a functional group that is reactive with an amino group, e.g., an epsilon amino group of a lysine residue, a free amino group at the N-terminus of a polypeptide, or any other amino group such as an amino group of asparagine, glutamine, arginine, or histidine.
In other embodiments, PEG is derivatized so that it is reactive with free carboxyl groups in the IFN-α polypeptide, e.g., the free carboxyl group at the carboxyl terminus of the IFN-α polypeptide. Suitable derivatives of PEG that are reactive with the free carboxyl group at the carboxyl-terminus of IFN-α include, but are not limited to PEG-amine, and hydrazine derivatives of PEG (e.g., PEG-NH—NH2).
In other embodiments, PEG is derivatized such that it comprises a terminal thiocarboxylic acid group, —COSH, which selectively reacts with amino groups to generate amide derivatives. Because of the reactive nature of the thio acid, selectivity of certain amino groups over others is achieved. For example, —SH exhibits sufficient leaving group ability in reaction with N-terminal amino group at appropriate pH conditions such that the ε-amino groups in lysine residues are protonated and remain non-nucleophilic. On the other hand, reactions under suitable pH conditions may make some of the accessible lysine residues to react with selectivity.
In other embodiments, the PEG comprises a reactive ester such as an N-hydroxy succinimidate at the end of the PEG chain. Such an N-hydroxysuccinimidate-containing PEG molecule reacts with select amino groups at particular pH conditions such as neutral 6.5-7.5. For example, the N-terminal amino groups may be selectively modified under neutral pH conditions. However, if the reactivity of the reagent were extreme, accessible-NH2 groups of lysine may also react.
The PEG can be conjugated directly to the IFN-α polypeptide, or through a linker. In some embodiments, a linker is added to the IFN-α polypeptide, forming a linker-modified IFN-α polypeptide. Such linkers provide various functionalities, e.g., reactive groups such sulfhydryl, amino, or carboxyl groups to couple a PEG reagent to the linker-modified IFN-α polypeptide.
In some embodiments, the PEG conjugated to the IFN-α polypeptide is linear. In other embodiments, the PEG conjugated to the IFN-α polypeptide is branched. Branched PEG derivatives such as those described in U.S. Pat. No. 5,643,575, “star-PEG's” and multi-armed PEG's such as those described in Shearwater Polymers, Inc. catalog “Polyethylene Glycol Derivatives 1997-1998.” Star PEGs are described in the art including, e.g., in U.S. Pat. No. 6,046,305.
PEG having a molecular weight in a range of from about 2 kDa to about 100 kDa, is generally used, where the term “about,” in the context of PEG, indicates that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight. For example, PEG suitable for conjugation to IFN-α has a molecular weight of from about 2 kDa to about 5 kDa, from about 5 kDa to about 10 kDa, from about 10 kDa to about 15 kDa, from about 15 kDa to about 20 kDa, from about 20 kDa to about 25 kDa, from about 25 kDa to about 30 kDa, from about 30 kDa to about 40 kDa, from about 40 kDa to about 50 kDa, from about 50 kDa to about 60 kDa, from about 60 kDa to about 70 kDa, from about 70 kDa to about 80 kDa, from about 80 kDa to about 90 kDa, or from about 90 kDa to about 100 kDa.
Preparing PEG-IFN-α Conjugates
As discussed above, the PEG moiety can be attached, directly or via a linker, to an amino acid residue at or near the N-terminus, internally, or at or near the C-terminus of the IFN-α polypeptide. Conjugation can be carried out in solution or in the solid phase.
N-Terminal Linkage
Methods for attaching a PEG moiety to an amino acid residue at or near the N-terminus of an IFN-α polypeptide are known in the art. See, e.g., U.S. Pat. No. 5,985,265.
In some embodiments, known methods for selectively obtaining an N-terminally chemically modified IFN-α are used. For example, a method of protein modification by reductive alkylation which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminus) available for derivatization in a particular protein can be used. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved. The reaction is performed at pH which allows one to take advantage of the pKa differences between the ε-amino groups of the lysine residues and that of the α-amino group of the N-terminal residue of the protein. By such selective derivatization attachment of a PEG moiety to the IFN-α is controlled: the conjugation with the polymer takes place predominantly at the N-terminus of the IFN-α and no significant modification of other reactive groups, such as the lysine side chain amino groups, occurs.
C-terminal Linkage
N-terminal-specific coupling procedures such as described in U.S. Pat. No. 5,985,265 provide predominantly monoPEGylated products. However, the purification procedures aimed at removing the excess reagents and minor multiply PEGylated products remove the N-terminal blocked polypeptides. In terms of therapy, such processes lead to significant increases in manufacturing costs. For example, examination of the structure of the well-characterized INFERGEN® Alfacon-1 CIFN polypeptide amino acid sequence reveals that the clipping is approximate 5% at the carboxyl terminus and thus there is only one major C-terminal sequence. Thus, in some embodiments, N-terminally PEGylated IFN-α is not used; instead, the IFN-α polypeptide is C-terminally PEGylated.
An effective synthetic as well as therapeutic approach to obtain mono PEGylated INFERGEN product is therefore envisioned as follows:
A PEG reagent that is selective for the C-terminal can be prepared with or without spacers. For example, polyethylene glycol modified as methyl ether at one end and having an amino function at the other end may be used as the starting material.
Preparing or obtaining a water-soluble carbodiimide as the condensing agent can be carried out. Coupling IFN-α (e.g., INFERGEN® Alfacon-1 CIFN or consensus interferon) with a water-soluble carbodiimide as the condensing reagent is generally carried out in aqueous medium with a suitable buffer system at an optimal pH to effect the amide linkage. A high molecular weight PEG can be added to the protein covalently to increase the molecular weight.
The reagents selected will depend on process optimization studies. A non-limiting example of a suitable reagent is EDAC or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. The water solubility of EDAC allows for direct addition to a reaction without the need for prior organic solvent dissolution. Excess reagent and the isourea formed as the by-product of the cross-linking reaction are both water-soluble and may easily be removed by dialysis or gel filtration. A concentrated solution of EDAC in water is prepared to facilitate the addition of a small molar amount to the reaction. The stock solution is prepared and used immediately in view of the water labile nature of the reagent. Most of the synthetic protocols in literature suggest the optimal reaction medium to be in pH range between 4.7 and 6.0. However the condensation reactions do proceed without significant losses in yields up to pH 7.5. Water may be used as solvent. In view of the contemplated use of INFERGEN, preferably the medium will be 2-(N-morpholino)ethane sulfonic acid buffer pre-titrated to pH between 4.7 and 6.0. However, 0.1M phosphate in the pH 7-7.5 may also be used in view of the fact that the product is in the same buffer. The ratios of PEG amine to the IFN-α molecule is optimized such that the C-terminal carboxyl residue(s) are selectively PEGylated to yield monoPEGylated derivative(s).
Even though the use of PEG amine has been mentioned above by name or structure, such derivatives are meant to be exemplary only, and other groups such as hydrazine derivatives as in PEG-NH—NH2 which will also condense with the carboxyl group of the IFN-α protein, can also be used. In addition to aqueous phase, the reactions can also be conducted on solid phase. Polyethylene glycol can be selected from list of compounds of molecular weight ranging from 300-40000. The choice of the various polyethylene glycols will also be dictated by the coupling efficiency and the biological performance of the purified derivative in vitro and in vivo i.e., circulation times, anti viral activities etc.
Additionally, suitable spacers can be added to the C-terminal of the protein. The spacers may have reactive groups such as SH, NH2 or COOH to couple with appropriate PEG reagent to provide the high molecular weight IFN-α derivatives. A combined solid/solution phase methodology can be devised for the preparation of C-terminal pegylated interferons. For example, the C-terminus of IFN-α is extended on a solid phase using a Gly-Gly-Cys-NH2 spacer and then monopegylated in solution using activated dithiopyridyl-PEG reagent of appropriate molecular weights. Since the coupling at the C-terminus is independent of the blocking at the N-terminus, the envisioned processes and products will be beneficial with respect to cost (a third of the protein is not wasted as in N-terminal PEGylation methods) and contribute to the economy of the therapy to treat chronic hepatitis C infections, liver fibrosis etc.
There may be a more reactive carboxyl group of amino acid residues elsewhere in the molecule to react with the PEG reagent and lead to monoPEGylation at that site or lead to multiple PEGylations in addition to the —COOH group at the C-terminus of the IFN-α. It is envisioned that these reactions will be minimal at best owing to the steric freedom at the C-terminal end of the molecule and the steric hindrance imposed by the carbodiimides and the PEG reagents such as in branched chain molecules. It is therefore the preferred mode of PEG modification for INFERGEN and similar such proteins, native or expressed in a host system, which may have blocked N-termini to varying degrees to improve efficiencies and maintain higher in vivo biological activity.
Another method of achieving C-terminal PEGylation is as follows. Selectivity of C-terminal PEGylation is achieved with a sterically hindered reagent which excludes reactions at carboxyl residues either buried in the helices or internally in IFN-α. For example, one such reagent could be a branched chain PEG 40kd in molecular weight and this agent could be synthesized as follows: OH3C—(CH2CH2O)n-CH2CH2NH2+ Glutamic Acid i.e., HOCO—CH2CH2CH(NH2)—COOH is condensed with a suitable agent e.g., dicyclohexyl carbodiimide or water-soluble EDC to provide the branched chain PEG agent OH3C—(CH2CH2O)n-CH2CH2NHCOCH(NH2)CH2OCH3—(CH2CH2O)n-CH2CH2NHCOCH2.
This reagent can be used in excess to couple the amino group with the free and flexible carboxyl group of IFN-α to form the peptide bond.
If desired, PEGylated IFN-α is separated from unPEGylated IFN-α using any known method, including, but not limited to, ion exchange chromatography, size exclusion chromatography, and combinations thereof. For example, where the PEG-IFN-α conjugate is a monoPEGylated IFN-α, the products are first separated by ion exchange chromatography to obtain material having a charge characteristic of monoPEGylated material (other multi-PEGylated material having the same apparent charge may be present), and then the monoPEGylated materials are separated using size exclusion chromatography.
MonoPEG (30 kD, linear)-ylated IFN-α
PEGylated IFN-α that is suitable for use in the present invention includes a monopegylated consensus interferon (CIFN) molecule comprised of a single CIFN polypeptide and a single polyethylene glycol (PEG) moiety, where the PEG moiety is linear and about 30 kD in molecular weight and is directly or indirectly linked through a stable covalent link-age to either the N-terminal residue in the CIFN polypeptide or a lysine residue in the CIFN polypeptide. In some embodiments, the monoPEG (30 kD, linear)-ylated IFN-α is monoPEG (30 kD, linear)-ylated consensus IFN-α.
In some embodiments, the PEG moiety is linked to either the alpha-amino group of the N-terminal residue in the CIFN polypeptide or the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide, thereby forming a hydrolytically stable linkage between the PEG moiety and the CIFN polypeptide.
In some embodiments, the PEG moiety is linked to the N-terminal residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the alpha-amino group of the N-terminal residue of the CIFN polypeptide.
In some embodiments, the PEG moiety is linked to a lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the lysine residue in the CIFN polypeptide.
In some embodiments, the PEG moiety is linked to a surface-exposed lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a surface-exposed lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, onlega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide.
In some embodiments, the PEG moiety is linked to a lysine chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 of the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 of the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.
In some embodiments, the PEG moiety is linked to a lysine chosen from lys121, lys134, lys135, and lys165 of the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine chosen from lys121, lys134, lys135, and lys165 of the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.
In connection with the above-described monopegylated CIFN molecules, the invention contemplates embodiments of each such molecule where the CIFN polypeptide is chosen from interferon alpha-con1, interferon alpha-con2, and interferon alpha-con3, the amino acid sequences of which CIFN polypeptides are disclosed in U.S. Pat. No. 4,695,623.
Populations of IFN-α
In addition, any of the methods of the invention can employ a PEGylated IFN-α composition that comprises a population of monopegylated IFN-α molecules, where the population consists of one or more species of monopegylated IFN-α molecules as described above. The subject composition comprises a population of modified IFN-α polypeptides, each with a single PEG molecule linked to a single amino acid residue of the polypeptide.
In some of these embodiments, the population comprises a mixture of a first IFN-α polypeptide linked to a PEG molecule at a first amino acid residue; and at least a second IFN-α polypeptide linked to a PEG molecule at a second amino acid residue, wherein the first and second IFN-α polypeptides are the same or different, and wherein the location of the first amino acid residue in the amino acid sequence of the first IFN-α polypeptide is not the same as the location of the second amino acid residue in the second IFN-α polypeptide. As one non-limiting example, an IFN-α composition suitable for use in a subject method comprises a population of PEG-modified IFN-α polypeptides, the population comprising an IFN-α polypeptide linked at its amino terminus to a linear PEG molecule; and an IFN-α polypeptide linked to a linear PEG molecule at a lysine residue.
Generally, a given modified IFN-α species represents from about 0.5% to about 99.5% of the total population of monopegylated IFNA polypeptide molecules in a population, e.g, a given modified IFN-α species represents about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 99.5% of the total population of monopegylated IFN-α polypeptide molecules in a population. In some embodiments, a suitable composition comprises a population of monopegylated IFN-α polypeptides, which population comprises at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, IFN-α polypeptides linled to PEG at the same site, e.g., at the N-terminal amino acid.
In particular embodiments of interest, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, the population consisting of one or more species of molecules, where each species of molecules is characterized by a single CIFN polypeptide linked, directly or indirectly in a covalent linkage, to a single linear PEG moiety of about 30 kD in molecular weight, and where the linkage is to either a lysine residue in the CIFN polypeptide, or the N-terminal amino acid residue of the CIFN polypeptide.
The amino acid residue to which the PEG is attached is in many embodiments the N-terminal amino acid residue. In other embodiments, the PEG moiety is attached (directly or via a linker) to a surface-exposed lysine residue. In additional embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 of the CIFN polypeptide. In further embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from lys121, lys134, lys135, and lys165 of the CIFN polypeptide.
As an example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety jinked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second nionopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A composition suitable for use in a subject method can further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
As another example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first surface-exposed lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A composition suitable for use in a subject method can further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
As another example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A composition suitable for use in a subject method can further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a second lysine residue selected from one of lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 in a third CIFN polypeptide, where the third CIFN polypeptide is the same or different from either of the first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence of the third CIFN polypeptide that is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition suitable for use in a subject method may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
As another example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of lys121, lys134, lys135, and lys165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A composition suitable for use in a subject method can further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a second lysine residue selected from one of lys121, lys134, lys135, and lys165 in a third CIFN polypeptide, where the third CIFN polypeptide is the same or different from either of the first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence of the third CIFN polypeptide that is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition suitable for use in a subject method may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys121, lys134, lys135, and lys165, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
As another non-limiting example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first lysine is located in a position in the amino acid sequence of the first CIEN polypeptide that is not the same as the position of the second lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition suitable for use in a subject method may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
As another non-limiting example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of the second CIFN polypeptide that is not the same as the position of the first lysine residue in the first CIFN polypeptide. The composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
As another non-limiting example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from lys121, lys134, lys135, and lys165 in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue chosen from lys121, lys134, lys135, and lys165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of the second CIFN polypeptide that is not the same as the position of the first lysine residue in the first CIFN polypeptide. The composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys121, lys134, lys135, and lys165, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
As another non-limiting example, a composition suitable for use in a subject method comprises a monopegylated population of CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first surface-exposed lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second surface-exposed lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first surface-exposed lysine is located in a position in the amino acid sequence of the first CIFN polypeptide that is not the same as the position of the second surface-exposed lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition suitable for use in a subject method may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
In connection with each of the above-described populations of monopegylated CIFN molecules, the invention contemplates embodiments where the molecules in each such population comprise a CIFN polypeptide chosen from interferon alpha-con1, interferon alpha-con2, and interferon alpha-con3.
The invention further features use of a product that is produced by the process of reacting CIFN polypeptide with a succinimidyl ester of alpha-methoxy, omega-propionylpoly(ethylene glycol) (mPEGspa) that is linear and about 30 kD in molecular weight, where the reactants are initially present at a molar ratio of about 1:1 to about 1:5 CIFN:mPEGspa, and where the reaction is conducted at a pH of about 7 to about 9, followed by recovery of the monopegylated CIFN product of the reaction. In one embodiment, the reactants are initially present at a molar ratio of about 1:3 CIFN:mPEGspa and the reaction is conducted at a pH of about 8. In another embodiment where the product is generated by a scaled-up procedure needed for toxicological and clinical investigations, the reactants are initially present in a molar ratio of 1:2 CIFN:nPEGspa and the reaction is conducted at a pH of about 8.0.
In connection with the above-described product-by-process, the invention contemplates embodiments where the CIFN reactant is chosen from interferon alpha-con1, interferon alpha-con2, and interferon alpha-con3.
IFN-β
The term interferon-beta (“IFN-β”) includes IFN-β polypeptides that are naturally occurring; non-naturally-occurring IFN-β polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-β that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-β.
Any of a variety of beta interferons can be administered in a subject method. Suitable beta interferons include, but are not limited to, naturally-occurring IFN-β; IFN-β1a, e.g., Avonex® (Biogen, Inc.), and Rebif® (Serono, SA); IFN-β1b (Betaseron®; Berlex); and the like.
The IFN-β formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-β.
IFN-β polypeptides can be produced by any known method. DNA sequences encoding IFN-β may be synthesized using standard methods. In many embodiments, IFN-β polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eulkaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-β is “recombinant IFN-β.” Where the host cell is a bacterial host cell, the IFN-β is modified to comprise an N-terminal methionine.
It is to be understood that IFN-β as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
IFN-tau
The term interferon-tau includes IFN-tau polypeptides that are naturally occurring; non-naturally-occurring IFN-tau polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-tau that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-tau.
Suitable tau interferons include, but are not limited to, naturally-occurring IFN-tau; Tauferon® (Pepgen Corp.); and the like.
IFN-tau may comprise an amino acid sequence as set forth in any one of GenBank Accession Nos. P15696; P56828; P56832; P56829; P56831; Q29429; Q28595; Q28594; S08072; Q08071; Q08070; Q08053; P56830; P28169; P28172; and P28171. The sequence of any known IFN-tau polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.
The IFN-tau formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-tau.
IFN-tau polypeptides can be produced by any known method. DNA sequences encoding IFN-tau may be synthesized using standard methods. In many embodiments, IFN-tau polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eulkaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-tau is “recombinant IFN-tau.” Where the host cell is a bacterial host cell, the IFN-tau is modified to comprise an N-terminal methionine.
It is to be understood that IFN-tau as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
IFN-ω
The term interferon-omega (“IFN-ω”) includes IFN-ω polypeptides that are naturally occurring; non-naturally-occurring IFN-ω polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-ω that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-ω.
Any known omega interferon can be administered in a subject method. Suitable IFN-ω include, but are not limited to, naturally-occurring IFN-ω; recombinant IFN-ω, e.g., Biomed 510 (BioMedicines); and the like.
IFN-ω may comprise an amino acid sequence as set forth in GenBank Accession No.
NP—002168; or AAA70091. The sequence of any known IFN-ω polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i. e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g, acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.
The IFN-ω formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-ω.
IFN-ω polypeptides can be produced by any known method. DNA sequences encoding IFN-ω may be synthesized using standard methods. In many embodiments, IFN-ω polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-ω is “recombinant IFN-ω.” Where the host cell is a bacterial host cell, the IFN-ω is modified to comprise an N-terminal methionine.
It is to be understood that IFN-ω as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
Type III Interferon Receptor Agonists
In any of the above-described methods, the interferon receptor agonist is in some embodiments an agonist of a Type III interferon receptor (e.g., “a Type III interferon agonist”). Type III interferon agonists include an IL-28b polypeptide; and IL-28a polypeptide; and IL-29 polypeptide; antibody specific for a Type III interferon receptor; and any other agonist of Type III interferon receptor, including non-polypeptide agonists.
IL-28A, IL-28B, and IL-29 (referred to herein collectively as “Type III interferons” or “Type III IFNs”) are described in Sheppard et al. (2003) Nature 4:63-68. Each polypeptide binds a heterodimeric receptor consisting of IL-10 receptor β chain and an IL-28 receptor α. Sheppard et al. (2003), supra. The amino acid sequences of IL-28A, IL-28B, and IL-29 are found under GenBank Accession Nos. NP—742150, NP—742151, and NP—742152, respectively.
The amino acid sequence of a Type III IFN polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids. Specific amino acid substitutions of interest include conservative and non-conservative changes. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
Included in the subject invention is the use of polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent. For examples, the backbone of the peptide may be cyclized to enhance stability (see Friedler et al.
J. Biol. Chem. 275:23783-23789). Analogs may be used that include residues other than naturally occurring L-amino acids, e.g. D-amino acids or non-naturally occurring synthetic amino acids. The protein may be pegylated to enhance stability. The polypeptides may be fused to albumin.
The polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the manner of preparation will be determined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cysteines can be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like.
Immunomodulatory Agents
Immunomodulatory agents that are suitable for use in a subject combination therapy include, but are not limited to, Type II interferon receptor agonists (including IFN-γ); TNF antagonists; pirfenidone and pirfenidone analogs; and thymosin-α.
Type II Interferon Receptor Agonists
Type II interferon receptor agonists include any naturally occurring or non-naturally-occurring ligand of a human Type II interferon receptor that binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.
A specific example of a Type II interferon receptor agonist is IFN-gamma (IFN-γ) and variants thereof. While the present invention exemplifies use of an IFN-gamma polypeptide, it will be readily apparent that any Type II interferon receptor agonist can be used in a subject method.
The nucleic acid sequences encoding IFN-gamma polypeptides may be accessed from public databases, e.g., Genbank, journal publications, and the like. While various mammalian IFN-gamma polypeptides are of interest, for the treatment of human disease, generally the human protein will be used. Human IFN-gamma coding sequence may be found in Genbank, accession numbers X13274; V00543; and NM—000619. The corresponding genomic sequence may be found in Genbank, accession numbers J00219; M37265; and V00536. See, for example. Gray et al. (1982) Nature 295:501 (Genbank X13274); and Rinderluiecht et al. (1984) J.B.C. 259:6790.
IFN-γ1b (Actimmune®; human interferon) is a single-chain polypeptide of 140 amino acids. It is made recombinantly in E. coli and is unglycosylated (Rinderkliecht et al. 1984, J. Biol. Chem. 259:6790-6797). Recombinant IFN-gamma as discussed in U.S. Pat. No. 6,497,871 is also suitable for use herein.
The IFN-gamma to be used in a subject method may be any of natural IFN-gamma, recombinant IFN-gamma and the derivatives thereof so far as they have an IFN-γ activity, particularly human IFN-gamma activity. Human IFN-gamma exhibits the antiviral and anti-proliferative properties characteristic of the interferons, as well as a number of other immunomodulatory activities, as is known in the art. Although IFN-gamma is based on the sequences as provided above, the production of the protein and proteolytic processing can result in processing variants thereof. The unprocessed sequence provided by Gray et al., supra, consists of 166 amino acids (aa). Although the recombinant IFN-gamma produced in E. coli was originally believed to be 146 amino acids, (commencing at amino acid 20) it was subsequently found that native human IFN-gamma is cleaved after residue 23, to produce a 143 aa protein, or 144 aa if the terminal methionine is present, as required for expression in bacteria. During purification, the mature protein can additionally be cleaved at the C terminus after reside 162 (referring to the Gray et al. sequence), resulting in a protein of 139 amino acids, or 140 amino acids if the initial methionine is present, e.g. if required for bacterial expression. The N-terminal methionine is an artifact encoded by the mRNA translational “start” signal AUG that, in the particular case of E. coli expression is not processed away. In other microbial systems or eukaryotic expression systems, methionine may be removed.
For use in the subject methods, any of the native IFN-gamma peptides, modifications and variants thereof, or a combination of one or more peptides may be used. IFN-gamma peptides of interest include fragments, and can be variously truncated at the carboxyl terminus relative to the full sequence. Such fragments continue to exhibit the characteristic properties of human gamma interferon, so long as amino acids 24 to about 149 (numbering from the residues of the unprocessed polypeptide) are present. Extraneous sequences can be substituted for the amino acid sequence following amino acid 155 without loss of activity. See, for example, U.S. Pat. No. 5,690,925. Native IFN-gamma moieties include molecules variously extending from amino acid residues 24-150; 24-151, 24-152; 24- 153, 24-155; and 24-157. Any of these variants, and other variants known in the art and having IFN-γ activity, may be used in the present methods.
The sequence of the IFN-γ polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e., will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids. Specific amino acid substitutions of interest include conservative and non-conservative changes. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation,.or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. IFN-gamma may be modified with one or more polyethylene glycol moieties (PEGylated). In one embodiment, the invention contemplates the use of IFN-gamma variants with one or more non-naturally occurring glycosylation and/or pegylation sites that are engineered to provide glycosyl- and/or PEG-derivatized polypeptides with reduced serum clearance, such as the IFN-gamma polypeptide variants described in any of International Patent Publication Nos. WO 01/36001 and WO 02/081507. Also included are modifications of glycosylation, e.g., those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g., by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g., phosphotyrosine, phosphoserine, or phosphothreonine.
Included in the subject invention is the use of IFN-γ polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent. For examples, the backbone of the peptide may be cyclized to enhance stability (see, for example, Friedler et al. 2000, J. Biol. Chem. 275:23783-23789). Analogs may be used that include residues other than naturally occurring L-amino acids, e.g., D-amino acids or non-naturally occurring synthetic amino acids. The protein may be pegylated to enhance stability.
The IFN-γ polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the method of preparation will be determined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cysteines can be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like.
The IFN-γ polypeptides may also be isolated and purified in accordance with conventional methods of recombinant synthesis. A lysate may be prepared of the expression host and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification technique. For the most part, the compositions which are used will comprise at least 20% by weight of the desired product, more usually at least about 75% by weight, preferably at least about 95% by weight, and for therapeutic purposes, usually at least about 99.5% by weight, in relation to contaminants related to the method of preparation of the product and its purification. Usually, the percentages will be based upon total protein.
TNF Antagonists
Suitable TNF-α antagonists for use herein include agents that decrease the level of TNF-α synthesis, agents that block or inhibit the binding of TNF-α to a TNF-α receptor (TNFR), and agents that block or inhibit TNFR-mediated signal transduction. Unless otherwise expressly stated, every reference to a “TNF-α antagonist” or “TNF antagonist” herein will be understood to mean a TNF-α antagonist other than pirfenidone or a pirfenidone analog.
As used herein, the terms “TNF receptor polypeptide” and “TNFR polypeptide” refer to polypeptides derived from TNFR (from any species) which are capable of binding TNF. Two distinct cell-surface TNFRs have described: Type II TNFR (or p75 TNFR or TNFRII) and Type I TNFR (or p55 TNFR or TNFRI). The mature full-length human p75 TNFR is a glycoprotein having a molecular weight of about 75-80 kilodaltons (kD). The mature full-length human p55 TNFR is a glycoprotein having a molecular weight of about 55-60 kD. Exemplary TNFR polypeptides are derived from TNFR Type I and/or TNFR type II. Soluble TNFR includes p75 TNFR polypeptide; fusions of p75 TNFR with heterologous fusion partners, e.g., the Fc portion of an immunoglobulin.
TNFR polypeptide may be an intact TNFR or a suitable fragment of TNFR. U.S. Pat. No. 5,605,690 provides examples of TNFR polypeptides, including soluble TNFR polypeptides, appropriate for use in the present invention. In many embodiments, the TNFR polypeptide comprises an extracellular domain of TNFR. In some embodiments, the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of TNFR linked to a constant domain of an immunoglobulin molecule. In other embodiments, the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of the p75 TNFR linked to a constant domain of an IgG1 molecule. In some embodiments, when administration to humans is contemplated, an Ig used for fusion proteins is human, e.g., human IgG1.
Monovalent and multivalent forms of TNFR polypeptides may be used in the present invention. Multivalent forms of TNFR polypeptides possess more than one TNF binding site. In some embodiments, the TNFR is a bivalent, or dimeric, form of TNFR. For example, as described in U.S. Pat. No. 5,605,690 and in Mohler et al., 1993, J. Tumunol., 151:1548-1561, a chimeric antibody polypeptide with TNFR extracellular domains substituted for the variable domains of either or both of the immunoglobulin heavy or light chains would provide a TNFR polypeptide for the present invention. Generally, when such a chimeric TNFR:antibody polypeptide is produced by cells, it forms a bivalent molecule through disulfide linkages between the immunoglobulin domains. Such a chimeric TNFR:antibody polypeptide is referred to as TNFR:Fc.
In one embodiment, a subject method involves administration of an effective amount of the soluble TNFR ENBREL® etanercept. ENBREL® is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) TNFR linked to the Fe portion of human IgG1. The Fc component of ENBREL® contains the CH2 domain, the CH3 domain and hinge region, but not the CH1 domain of IgG1. ENBREL® is produced in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. Smith et al. (1990) Science 248:1019-1023; Mohler et al. (1993) J. Immunol. 151:1548-1561; U.S. Pat. No. 5,395,760; and U.S. Pat. No. 5,605,690.
Also suitable for use are monoclonal antibodies that bind TNF-α. Monoclonal antibodies include “humanized” mouse monoclonal antibodies; chimeric antibodies; monoclonal antibodies that are at least about 80%, at least about 90%, at least about 95%, or 100% human in amino acid sequence; and the like. See, e.g., WO 90/10077; WO 90/04036;
and WO 92/02190. Suitable monoclonal antibodies include antibody fragments, such as Fv, F(ab′)2 and Fab; synthetic antibodies; artificial antibodies; phage display antibodies; and the like.
Examples of suitable monoclonal antibodies include infliximab (REMICADE®, Centocor); and adalimumab (HUMIRA™, Abbott). REMICADE® is a chimeric monoclonal anti-TNF-α antibody that includes about 25% mouse amino acid sequence and about 75% human amino acid sequence. REMICADE® comprises a variable region of a mouse monoclonal anti-TNF-α antibody fused to the constant region of a human IgG1. Elliott et al. (1993) Arthritis Rheum. 36:1681-1690; Elliott et al. (1994) Lancet 344:1105-1110; Baert et al. (1999) Gastroenterology 116:22-28. HUMIRA™ is a human, full-length IgG1 monoclonal antibody that was identified using phage display technology. Piascik (2003) J. Am. Pharm. Assoc. 43:327-328.
Also included in the term “TNF antagonist,” and therefore suitable for use in a subject method, are stress-activated protein kinase (SAPK) inhibitors. SAPK inhibitors are known in the art, and include, but are not limited to 2-alkyl imidazoles disclosed in U.S. Pat. No. 6,548,520; 1,4,5-substituted imidazole compounds disclosed in U.S. Pat. No. 6,489,325; 1,4,5-substituted imidazole compounds disclosed in U.S. Pat. No. 6,569,871; heteroaryl aminophenyl ketone compounds disclosed in Published U.S. Patent Application No. 2003/0073832; pyridyl imidazole compounds disclosed in U.S. Pat. No. 6,288,089; and heteroaryl aminobenzophenones disclosed in U.S. Pat. No. 6,432,962. Also of interest are compounds disclosed in U.S. Patent Application Publication No. 2003/0149041; and U.S. Pat. No. 6,214,854. A stress-activated protein kinase is a member of a family of nitrogen-activated protein kinases which are activated in response to stress stimuli. SAPK include, but are not limited to, p38 (Lee et al. (1994) Nature 372:739) and c-jun N-terminal kinase (JNK).
Methods to assess TNF antagonist activity are known in the art and exemplified herein. For example, TNF antagonist activity may be assessed with a cell-based competitive binding assay. In such an assay, radiolabeled TNF is mixed with serially diluted TNF antagonist and cells expressing cell membrane bound TNFR. Portions of the suspension are centrifuged to separate free and bound TNF and the amount of radioactivity in the free and bound fractions determined. TNF antagonist activity is assessed by inhibition of TNF binding to the cells in the presence of the TNF antagonist.
As another example, TNF antagonists may be analyzed for the ability to neutralize TNF activity in vitro in a bioassay using cells susceptible to the cytotoxic activity of TNF as target cells. In such an assay, target cells, cultured with TNF, are treated with varying amounts of TNF antagonist and subsequently are examined for cytolysis. TNF antagonist activity is assessed by a decrease in TNF-induced target cell cytolysis in the presence of the TNF antagonist.
Pirfenidone and Analogs Thereof
In some embodiments, the subject method provides an immunomodulatory agent that is pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) or a pirfenidone analog.
Pirfenidone
Pirfenidone Analogs
Descriptions for Substituents R1, R2, X
R1: carbocyclic (saturated and unsaturated), heterocyclic (saturated or unsaturated), alkyls (saturated and unsaturated). Examples include phenyl, benzyl, pyrimidyl, naphthyl, indolyl, pyrrolyl, furyl, thienyl, imidazolyl, cyclohexyl, piperidyl, pyrrolidyl, morpholinyl, cyclohexenyl, butadienyl, and the like.
R1 can further include substitutions on the carbocyclic or heterocyclic moieties with substituents such as halogen, nitro, amino, hydroxyl, alkoxy, carboxyl, cyano, thio, alkyl, aryl, heteroalkyl, heteroaryl and combinations thereof, for example, 4-nitrophenyl, 3-chliorophenyl, 2,5-dinitrophenyl, 4-metlioxyphenyl, 5-methyl-pyrrolyl, 2, 5-diclilorocyclohexyl, guanidinyl-cyclohexenyl and the like.
R2: alkyl, carbocylic, aryl, heterocyclic. Examples include: methyl, ethyl, propyl, isopropyl, phenyl, 4-nitrophenyl, thienyl and the like.
X: may be any number (from 1 to 3) of substituents on the carbocyclic or heterocyclic ring. The substituents can be the same or different. Substituents can include hydrogen, alklyl, heteroalkyl, aryl, heteroaryl, halo, nitro, carboxyl, hydroxyl, cyano, amino, thio, alklylamino, haloaryl and the like.
The substituents may be optionally further substituted with 1-3 substituents from the group consisting of alkyl, aryl, nitro, alkoxy, hydroxyl and halo groups. Examples include: methyl, 2,3-dimethyl, phenyl, p-tolyl, 4-chlorophenyl, 4-nitrophenyl, 2,5-dichlorophenyl, furyl, thienyl and the like.
Specific Examples include those shown in Table 1:
5-Methyl-1-(2′-pyridyl)-2-(1H) pyridine,
6-Methyl-1-phenyl-2-(1H) pyridone,
5-Methyl-3-phenyl-1-(2′-thienyl)-2-(1H) pyridone,
5-Methyl-1-(2′-naphthyl)-2-(1H) pyridone,
5-Methyl-1-p-tolyl-2-(1H) pyridone,
5-Methyl-1-(1′naphthyl)-2-(1H) pyridone,
5-Ethyl-1-phenyl-2-(1H) pyridone,
5-Methyl-1-(5′-quinolyl)-2-(1H) pyridone,
5-Methyl-1-(4′-pyridyl)-2-(1H) pyridone,
5-Methyl-1-(4′-methoxyphenyl)-2-(1H) pyridone,
1-Phenyl-2-(1H) pyridone,
1,3-Diphenyl-2-(1H) pyridone,
1,3-Diphenyl-5-methyl-2-(1H) pyridone,
5-Methyl-1-(3′-trifluoromethylphenyl)-2-(1H)-pyridone,
5-Methyl-1-(3-nitrophenyl)-2-(1H) pyridone,
3-(4′-Chlorophenyl)-5-Methyl-1-phenyl-2-(1H) pyridone,
5-Methyl-1-(2′-Thienyl)-2-(1H) pyridone,
5-Methyl-1-(2′-thiazolyl)-2-(1H) pyridone,
3,6-Dimethyl-1-phenyl-2-(1H) pyridone,
1-(4′Chlorophenyl)-5-Methyl-2-(1H) pyridone,
1-(2′-Imidazolyl)-5-Methyl-2-(1H) pyridone,
1-(4′-Nitrophenyl)-2-(1H) pyridone,
1-(2′-Furyl)-5-Methyl-2-(1H) pyridone,
1-Phenyl-3-(4′-chlorophenyl)-2-(1H) pyridine.
1-Phenyl-3-(1H) pyridine,
1-(4′-Chlorophenyl)-5-methyl-3-(1H) pyridine.
U.S. Pat. Nos. 3,974,281; 3,839,346; 4,042,699; 4,052,509; 5,310,562; 5,518,729; 5,716,632; and 6,090,822 describe methods for the synthesis and formulation of pirfenidone and pirfenidone analogs in pharmaceutical compositions suitable for use in the methods of the present invention.
Thymosin-α
Thymosin-α (Zadaxin™; available from SciClone Pharmaceuticals, Inc., San Mateo, Calif.) is a synthetic form of thymosin alpha 1, a hormone found naturally in the circulation and produced by the thymus gland. Thymosin-α increases activity of T cells and NK cells. Zadaxin™ formulated for subcutaneous injection is a purified sterile lyophilized preparation of chemically synthesized thymosin alpha 1 identical to human thymoisin alpha 1. Thymosin alpha 1 is an acetylated polypeptide with the following sequence: Ac-Ser-Asp-Ala-Ala-Val -Asp-Thr-Ser-Ser-Glu-lle-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu -Val-Val-Glu-Glu-Ala-Glu-Asn-OH, and having a molecular weight of 3,108 daltons. The lyophilized preparation contains 1.6 mg synthetic thymoosin-α, 50 mg mannitol, and sodium phosphate buffer to adjust the pH to 6.8.
Ribavirin, 1-β-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is a nucleoside analog available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif., and is described in the Merck Index, compound No. 8199, Eleventh Edition. Its manufacture and formulation is described in U.S. Pat. No. 4,211,771. The invention also contemplates use of derivatives of ribavirin (see, e.g., U.S. Pat. No. 6,277,830). The ribavirin may be administered orally in capsule or tablet form, or in the same or different administration form and in the same or different route as another therapeutic agent administered in a subject combination therapy. Of course, other types of administration of ribavirin, as they become available are contemplated, such as by nasal spray, transdermally, by suppository, by sustained release dosage form, etc. Any form of administration will work so long as the proper dosages are delivered without destroying the active ingredient.
Ribavirin is generally administered in an amount ranging from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day. In some embodiments, ribavirin is administered throughout the entire course of the combination therapy. In other embodiments, ribavirin is administered only during a first period of time. In still other embodiments, ribavirin is administered only during a second period of time.
Levovirin
Levovirin is the L-enantiomer of ribavirin, and exhibits the property of enhancing a Th1 immune response over a Th2 immune response. Levovirin is manufactured by ICN Pharmaceuticals.
Levovirin has the following structure:
Viramidine
Viramidine is a 3-carboxamidine derivative of ribavirin, and acts as a prodrug of ribavirin. It is efficiently converted to ribavirin by adenosine deaminases.
Viramidine has the following structure:
Nucleoside Analogs
Nucleoside analogs that are suitable for use in a subject combination therapy include, but are not limited to, ribavirin, levovirin, viramidine, isatoribine, an L-ribofuranosyl nucleoside as disclosed in U.S. Pat. No. 5,559,101 and encompassed by Formula I of U.S. Pat. No. 5,559,101 (e.g., 1-β-L-ribofuranosyluracil, 1-β-L-ribofuranosyl-5-fluorouracil, 1-β-L-ribofuranosylcytosine, 9-β-L-ribofuranosyladenine, 9-β-L-ribofuranosylhypoxanthine, 9-β-L-ribofuranosylguanine, 9-β-L-ribofuranosyl-6-thioguainie, 2-amino-α-L-ribofuranl[1′,2′:4,5]oxazoline, O2,O2-anhydro-1-α-L-ribofuranosyluracil, 1-α-L-ribofuranosyluracil, 1-(2,3,5-tri-O-benzoyl-α-ribofuranosyl)-4-thiouracil, 1-α-L-ribofuranosylcytosine, 1-α-L-ribofuranosyl-4-thiouracil, 1-α-L-ribofaranosyl-5-fluorouracil, 2-amino-β-L-arabinofurano [1′,2′:4,5]oxazoline, O2,O2-anhydro-β-L-arabinofuranosyluracil, 2′-deoxy-β-L-uridine, 3′5′-Di-O-benzoyl-2′deoxy-4-thio β-L-uridine, 2′-deoxy-β-L-cytidine, 2′-deoxy-β-L-4-thiouridine, 2′-deoxy-β-L-thymidine, 2′-deoxy-β-L-5-fluorouridine, 2′,3′-dideoxy-β-L-uridine, 2′-deoxy-β-L-5-fluorouridine, and 2′-deoxy-β-L-inosine); a compound as disclosed in U.S. Pat. No. 6,423,695 and encompassed by Formula I of U.S. Pat. No. 6,423,695; a compound as disclosed in U.S. Patent Publication No. 2002/0058635, and encompassed by Formula 1 of U.S. Patent Publication No. 2002/0058635; a nucleoside analog as disclosed in WO 01/90121 A2 (Idenix); a nucleoside analog as disclosed in WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.); a nucleoside analog as disclosed in WO 02/057287 A2 or WO 02/057425 A2 (both MercklIsis); and the like.
HCV NS3 Inhibitors
Suitable HCV non-structural protein-3 (NS3) inhibitors include, but are not limited to, a tri-peptide as disclosed in U.S. Pat. Nos. 6,642,204, 6,534,523, 6,420,380, 6,410,531, 6,329,417, 6,329,379, and 6,323,180 (Boehringer-Ingelheim); a compound as disclosed in U.S. Pat. No. 6,143,715 (Boehringer-Ingelheim); a macrocyclic compound as disclosed in U.S. Pat. No. 6,608,027 (Boehringer-Ingelheim); an NS3 inhibitor as disclosed in U.S. Pat. Nos. 6,617,309, 6,608,067, and 6,265,380 (Vertex Pharmaceuticals); an azapeptide compound as disclosed in U.S. Pat. No. 6,624,290 (Schering); a compound as disclosed in U.S. Pat. No. 5,990,276 (Schering); a compound as disclosed in Pause et al. (2003) J. Biol. Chem. 278:20374-20380; NS3 inhibitor BILN 2061 (Boehringer-Ingelheim; Lamarre et al. (2002) Hepatology 36:301A; and Lamarre et al. (Oct. 26, 2003) Nature doi:10.1038/nature02099); NS3 inhibitor VX-950 (Vertex Pharmaceuticals; Kwong et al. (Oct. 24-28, 2003) 54th Ann. Meeting AASLD); NS3 inhibitor SCH6 (Abib et al. (Oct. 24-28, 2003) Abstract 137. Program and Abstracts of the 54th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). Oct. 24-28, 2003. Boston, Mass.); any of the NS3 protease inhibitors disclosed in WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO 00/59929 or WO 02/060926 (e.g., compounds 2, 3, 5, 6, 8, 10, 11, 18, 19, 29, 30, 31, 32, 33, 37, 38, 55, 59, 71, 91, 103, 104, 105, 112, 113, 114, 115, 116, 120, 122, 123, 124, 125, 126 and 127 disclosed in the table of pages 224-226 in WO 02/060926); an NS3 protease inhibitor as disclosed in any one of U.S. Patent Publication Nos. 2003019067, 20030187018, and 20030186895; and the like.
Of particular interest in many embodiments are NS3 inhibitors that are specific NS3 inhibitors, e.g., NS3 inhibitors that inhibit NS3 serine protease activity and that do not show significant inhibitory activity against other serine proteases such as human leukocyte elastase, porcine pancreatic elastase, or bovine pancreatic chymotrypsin, or cysteine proteases such as human liver cathepsin B.
NS5B Inhibitors
Suitable HCV non-structural protein-5 (NS5; RNA-dependent RNA polymerase) inhibitors include, but are not limited to, a compound as disclosed in U.S. Pat. No. 6,479,508 (Boeliringer-Ingelheim); a compound as disclosed in any of International Patent Application Nos. PCT/CA02/01127, PCT/CA02/01128, and PCT/CA02/01129, all filed on Jul. 18, 2002 by Boehringer Ingelheim; a compound as disclosed in U.S. Pat. No. 6,440,985 (ViroPharma); a compound as disclosed in WO 01/47883, e.g., JTK-003 (Japan Tobacco); a dinucleotide analog as disclosed in Zhong et al. (2003) Antimicrob. Agents Chemother. 47:2674-268 1; a benzothiadiazine compound as disclosed in Dhanalc et al. (2002) J. Biol Chem. 277(41):38322-7; an NS5B inhibitor as disclosed in WO 02/100846 A1 or WO 02/100851 A2 (both Shire); an NS5B inhibitor as disclosed in WO 01/85172 A1 or WO 02/098424 A1 (both Glaxo SmithKline); an NS5B inhibitor as disclosed in WO 00/06529 or WO 02/06246 A1 (both Merck); an NS5B inhibitor as disclosed in WO 03/000254 (Japan Tobacco); an NS5B inhibitor as disclosed in EP 1 256,628 A2 (Agouron); JTK-002 (Japan Tobacco); JTK-109 (Japan Tobacco); and the like.
Of particular interest in many embodiments are NS5 inhibitors that are specific NS5 inhibitors, e.g., NS5 inhibitors that inhibit NS5 RNA-dependent RNA polymerase and that lack significant inhibitory toward other RNA dependent RNA polymerases and toward DNA dependent RNA polymerases.
Additional Antiviral Therapeutic Agents
Additional antiviral therapeutic agents that can be administered in a subject combination therapy include, but are not limited to, inhibitors of inosine monophosphate dehydrogenase (IMPDH); ribozymes that are complementary to viral nucleotide sequences; antisense RNA inhibitors; and the like.
IMPDH inhibitors
IMPDH inhibitors that are suitable for use in a subject combination therapy include, but are not limited to, VX-497 ((S)—N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)-ureido]-benzyl-carbamic acid tetrahydrofuran-3-yl-ester); Vertex Pharmaceuticals; see, e.g., Marldand et al. (2000) Antimicrob. Agents Chemother. 44:859-866); ribavirin (ICN Pharmaceuticals);
levovirin (Ribapharm; see, e.g., Watson (2002) Curr Opin Investig Drugs 3(5):680-3); viramidine (Ribapharm); and the like.
Ribozyme and Antisense
Ribozyme and antisense antiviral agents that are suitable for use in a subject combination therapy include, but are not limited to, ISIS 14803 (ISIS Pharmaceuticals/Elan Corporation; see, e.g., Witherell (2001) Curr Opin Investig Drugs. 2(11):1523-9); Heptazyme™; and the like.
Side Effect Management Agents
In some embodiments, a subject therapy comprises administering a palliative agent (e.g., an agent that reduces patient discomfort caused by a therapeutic agent), or other agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent. Such agents are also referred to as “side effect management agents.”
Suitable side effect management agents include agents that are effective in pain management; agents that ameliorate gastrointestinal discomfort; analgesics, anti-inflammatories, antipsychotics, antineurotics, anxiolytics, and hematopoietic agents. In addition, the invention contemplates the use of any compound for palliative care of patients suffering from pain or any other side effect in the course of treatment with a subject therapy. Exemplary palliative agents include acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.
Analgesics that can be used to alleviate pain in the methods of the invention include non-narcotic analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) acetaminophen, salicylate, acetyl-salicylic acid (aspirin, diflunisal), ibuprofen, Motrin, Naprosyn, Nalfon, and Trilisate, indomethacin, glucametacine, acemetacin, sulindac, naproxen, piroxicam, diclofenac, benoxaprofen, ketoprofen, oxaprozin, etodolac, letorolac tromethamine, kcetorolac, nabumetone, and the like, and mixtures of two or more of the foregoing.
Other suitable analgesics include fentanyl, buprenorphine, codeine sulfate, morphine hydrochloride, codeine, hydromorphone (Dilaudid), levorphanol (Levo-Dromoran), methadone (Dolophine), morphine, oxycodone (in Percodan), and oxymorphone (Numorphan). Also suitable for use are benzodiazepines including, but not limited to, flurazepain (Dalmane), diazepain (Valium), and Versed, and the like.
Suitable anti-inflammatory agents include, but are not limited to, steroidal anti-inflammatory agents, and non-steroidal anti-inflammatory agents.
Suitable steroidal anti-inflammatory agents include, but are not limited to, hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, conisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures of two or more of the foregoing.
Suitable non-steroidal anti-inflammatory agents, include, but are not limited to, 1) the oxicams, such as piroxicam, isoxicam, tenoxicam, and sudoxicamn; 2) the salicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal; and fendosal; 3) the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, and felbinac; 4) the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; 5) the propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and 6) the pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone, mixtures of these non-steroidal anti-inflammatory agents may also be employed, as well as the pharmaceutically-acceptable salts and esters of these agents.
Suitable anti-inflammatory agents include, but are not limited to, Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; -Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; −Diflumidone Sodium; Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone; Enlimomab Enolicam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort; Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen; Furobufen; Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen; Lofemizole Hydrochloride; Lomoxicam; Loteprednol Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; Methylprednisolone Suleptanate; Morniflumate; Nabumetone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidone; Piroxicam; Piroxicam Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone; Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex; Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone; Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin; Zomepirac Sodium.
Antipsychotic and antineurotic drugs that can be used to alleviate psychiatric side effects in the methods of the invention include any and all selective serotonin receptor inhibitors (SSRIs) and other anti-depressants, anxiolytics (e.g. alprazolam), etc. Anti-depressants include, but are not limited to, serotonin reuptake inhibitors such as Celexa®, Desyrel®, Effexor®, Luvox®, Paxil®, Prozac®, Zoloft®, and Serzone®; tricyclics such as Adapin®, Anafrinil®, Elavil®, Janimmine®, Ludiomil®, Pamelor®, Tofranil®, Vivactil®, Sinequan®, and Surmontil®; monoamine oxidase inhibitors such as Eldepryl®, Marplan®, Nardil®, and Parnate®. Anti-anxiety agents include, but are not limited to, azaspirones such as BuSpar®, benzodiazepines such as Ativan®, Librium®, Tranxene®, Centrax®, Klonopin®, Paxipam®, Serax®, Valium®, and Xanax®; and beta-blockers such as Inderal® and Tenormin®.
Agents that reduce gastrointestinal discomfort such as nausea, diarrhea, gastrointestinal cramping, and the like are suitable palliative agents for use in a subject combination therapy. Suitable agents include, but are not limited to, antiemetics, anti-diarrheal agents, H2 blockers, antacids, and the like.
Suitable H2 blockers (histamine type 2 receptor antagonists) that are suitable for use as a palliative agent in a subject therapy include, but are not limited to, Cimetidine (e.g., Tagamet, Peptol, Nu-cimet, apo-cimetidine, non-cimetidine); Ranitidine (e.g., Zantac, Nu-ranit, Novo-randine, and apo-ranitidine); and Famotidine (Pepcid, Apo-Famotidine, and Novo-Famotidine).
Suitable antacids include, but are not limited to, aluminum and magnesium hydroxide (Maalox®, Mylanta®; aluminum carbonate gel (Basajel®; aluminum hydroxide (Amphojel®, AlternaGEL®); calcium carbonate (Tums®, Titralac®); magnesium hydroxide; and sodium bicarbonate.
Antiemetics include, but are not limited to, 5-hydroxytryptophan-3 (5HT3) inhibitors; corticosteroids such as dexamethasone and methylprednisolone; Marinol® (dronabinol); prochlolperazine; benzodiazepines; promethazine; and metoclopramide cisapride; Alosetron Hydrochloride; Batanopride Hydrochloride; Bemesetron; Benzquinamide; Chlorpromazine; Chlorpromazine Hydrochloride; Clebopride; Cyclizine Hydrochloride; Dimenhydrinate; Diphenidol; Diphenidol Hydrochloride; Diphenidol Pamoate; Dolasetron Mesylate; Domperidone; Dronabinol; Fludorex; Flumeridone; Galdansetron Hydrochloride; Granisetron; Granisetron Hydrochloride; Lurosetron Mesylate; Meclizine Hydrochloride; Metoclopramide Hydrochloride; Metopimazine; Ondansetron Hydrochloride; Pancopride; Prochlorperazine; Prochlorperazine Edisylate; Prochlorperazine Maleate; Prometliazine Hydrochloride; Thiethylperazine; Thiethylperazine Malate; Thiethylperazine Maleate; Trimethobenzamide Hydrochloride; Zacopride Hydrochloride.
Anti-diarrheal agents include, but are not limited to, Rolgamidine, Diphenoxylate hydrochloride (Lomotil), Metronidazole (Flagyl), Methylprednisolone (Medrol), Sulfasalazine (Azulfidine), and the like.
Suitable hematopoietic agents that can be used to prevent or restore depressed blood cell populations in the methods of the invention include erythropoietins, such as EPOGEN™ epoetin-alfa, granulocyte colony stimulating factors (G-CSFs), such as NEUPOGEN™ filgrastim, granulocyte-macrophage colony stimulating factors (GM-CSFs), thrombopoietins, etc.
Dosages, Formulations, and Route of Administration
A therapeutic agent (also referred to as an “active agent”) used in a subject method, e.g., i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; iii) an inhibitor of an HCV enzyme, is administered to individuals in a formulation with a pharmaceutically acceptable excipient(s). A wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) “Remington: The Science and Practice of Pharmacy,” 20th edition, Lippincott, Williams, & Wilkins Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H. C. Ansel et al., eds., 7th ed., Lippincott, Williams, & Wilkins and Handbook of Pharmaceutical Excipients (2000) A. H. Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc.
The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
In the subject methods, the active agents (e.g., (i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; iii) an inhibitor of an HCV enzyme; and optionally one or more additional active agents) may be administered to the host using any convenient means capable of resulting in the desired therapeutic effect. Thus, the agents can be incorporated into a variety of formulations for therapeutic administration. More particularly, and active agent (e.g., (i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; iii) an inhibitor of an HCV enzyme; and optionally one or more additional active agents) can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.
As such, administration of an active agent (e.g., (i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; iii) an inhibitor of an HCV enzyme; and optionally one or more additional active agents) can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal, etc., administration. In some embodiments, two different routes of administration are used. For example, in some embodiments, IFN-α is administered subcutaneously, and pirfenidone is administered orally.
Subcutaneous administration of an active agent (e.g., (i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; iii) an inhibitor of an HCV enzyme; and optionally one or more additional active agents) can be accomplished using standard methods and devices, e.g., needle and syringe, a subcutaneous injection port delivery system, and the like. See, e.g., U.S. Pat. Nos. 3,547,119; 4,755,173;
4,531,937; 4,311,137; and 6,017,328. A combination of a subcutaneous injection port and a device for administration of a therapeutic agent to a patient through the port is referred to herein as “a subcutaneous injection port delivery system.” In some embodiments, subcutaneous administration is achieved by a combination of devices, e.g., bolus delivery by needle and syringe, followed by delivery using a continuous delivery system.
In some embodiments, a therapeutic agent, e.g., i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; iii) an inhibitor of an HCV enzyme, is delivered by a continuous delivery system. The term “continuous delivery system” is used interchangeably herein with “controlled delivery system” and encompasses continuous (e.g., controlled) delivery devices (e.g., pumps) in combination with catheters, injection devices, and the like, a wide variety of which are known in the art.
Mechanical or electromechanical infusion pumps can also be suitable for use with the present invention. Examples of such devices include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852; 5,820,589; 5,643,207; 6,198,966; and the like. In general, the present methods of drug delivery can be accomplished using any of a variety of refillable, pump systems. Pumps provide consistent, controlled release over time. Typically, the agent is in a liquid formulation in a drug-impermeable reservoir, and is delivered in a continuous fashion to the individual.
In one embodiment, the drug delivery system is an at least partially implantable device. The implantable device can be implanted at any suitable implantation site using methods and devices well known in the art. All implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body. Subcutaneous implantation sites are generally preferred because of convenience in implantation and removal of the drug delivery device.
Drug release devices suitable for use in the invention may be based on any of a variety of modes of operation. For example, the drug release device can be based upon a diffusive system, a convective system, or an erodible system (e.g., an erosion-based system). For example, the drug release device can be an electrochemical pump, osmotic pump, an electroosmotic pump, a vapor pressure pump, or osmotic bursting matrix, e.g., where the drug is incorporated into a polymer and the polymer provides for release of drug formulation concomitant with degradation of a drug-impregnated polymeric material (e.g., a biodegradable, drug-impregnated polymeric material). In other embodiments, the drug release device is based upon an electrodiffusion system, an electrolytic pump, an effervescent pump, a piezoelectric pump, a hydrolytic system, etc.
Drug release devices based upon a mechanical or electronmechanical infusion pump can also be suitable for use with the present invention. Examples of such devices include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852, and the like. In general, a subject treatment method can be accomplished using any of a variety of refillable, non-exchangeable pump systems. Pumps and other convective systems will in some embodiments be used, due to their generally more consistent, controlled release over time. Osmotic pumps are particularly preferred due to their combined advantages of more consistent controlled release and relatively small size (see, e.g., PCT published application no. WO 97/27840 and U.S. Pat. Nos. 5,985,305 and 5,728,396)). Exemplary osmotically-driven devices suitable for use in the invention include, but are not necessarily limited to, those described in U.S. Pat. Nos. 3,760,984; 3,845,770; 3,916,899; 3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880; 4,036,228; 4,111,202; 4,111,203; 4,203,440; 4,203,442; 4,210,139; 4,327,725; 4,627,850; 4,865,845; 5,057,318; 5,059,423; 5,112,614; 5,137,727; 5,234,692; 5,234,693; 5,728,396; and the like.
In some embodiments, the drug delivery device is an implantable device. The drug delivery device can be implanted at any suitable implantation site using methods and devices well known in the art. As noted infra, an implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body.
In some embodiments, a therapeutic agent (e.g., (i) a Type I interferon receptor agonist or a Type III interferon receptor agonist; ii) an immunomodulatory agent; iii) an inhibitor of an HCV enzyme; and optionally one or more additional active agents) is delivered using an implantable drug delivery system, e.g., a system that is programmable to provide for administration of a therapeutic agent. Exemplary programmable, implantable systems include implantable infusion pumps. Exemplary implantable infusion pumps, or devices useful in connection with such pumps, are described in, for example, U.S. Pat. Nos. 4,350,155; 5,443,450; 5,814,019; 5,976,109; 6,017,328; 6,171,276; 6,241,704; 6,464,687; 6,475,180; and 6,512,954. A further exemplary device that can be adapted for the present invention is the Synchromed infusion pump (Medtronic).
In pharmaceutical dosage forms, the active agents may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and are in no way limiting.
For oral preparations, the active agents can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.
The active agents can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
Furthermore, the active agents can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. An active agent can can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.
Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more inhibitors. Similarly, unit dosage forms for injection or intravenous administration may comprise the inhibitor(s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.
The term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of an active agent calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle. The specifications for a particular active agent depend on the particular agent employed and the effect to be achieved, and the pharmacodynamics associated with each agent in the host.
In connection with each of the methods described herein, the invention provides embodiments in which the therapeutic agent(s) is/are administered to the patient by a controlled drug delivery device. In some embodiments, the therapeutic agent(s) is/are delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver the therapeutic agent(s) to the patient substantially continuously or continuously by subcutaneous infusion.
In other embodiments, a therapeutic agent is administered to the patient so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the monotherapy or combination therapy. Optionally, an implantable infusion pump is used to deliver the therapeutic agent to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the therapeutic agent in monotherapy or combination therapy.
Type I or Type III interferon receptor agonist
In some embodiments, the Type I or III interferon receptor agonist is an IFN-α. Effective dosages of an IFN-α can range from about 1 μg to about 30 μg, from about 3 μg to about 27 μg, from about 1 MU to about 20 MU, from about 3 MU to about 10 MU, from about 90 μg to about 180 μg, or from about 18 μg to about 90 μg.
Effective dosages of Infergen consensus IFN-α include about 3 μg, about 9 μg, about 15 μg, about 18 μg, or about 27 μg of drug per dose. Effective dosages of IFN-α2a and IFN-α2b can range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGylated IFN-α2a can contain an amount of about 90 μg to 180 μg, or about 135 μg, of drug per dose. Effective dosages of PEGylated IFN-α2b can contain an amount of about 0.5 μg to 1.5 μg of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 10 μg to about 100 μg, or about 18 μg to about 90 μg, or about 27 μg to about 60 μg, or about 45 μg, of CIFN amino acid weight per dose of PEG-CIFN. IFN-α can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
In some embodiments, monoPEG (30 kD, linear)-ylated consensus IFN-α is administered. In some embodiments, monoPEG (30 kD, linear)-ylated consensus IFN-α is administered at a dosing interval of every 7 days. In some embodiments, monoPEG (30 kD, linear)-ylated consensus IFN-α is administered at a dosing interval of every 8 days to every 14 days, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. Effective dosages of monoPEG (30 kD, linear)-ylated INFERGEN® consensus IFN-α generally range from about 45 μg to about 270 μg per dose, e.g., 60 μg per dose, 100 μg per dose, 150 μg per dose, 200 μg per dose, etc.
In some embodiments, a Type I or III interferon receptor agonist is administered in a first dosing regimen, followed by a second dosing regimen. The first dosing regimen of Type I or III interferon receptor agonist (also referred to as “the induction regimen ”) generally involves administration of a higher dosage of the Type I or III interferon receptor agonist. For example, in the case of INFERGEN® consensus IFN-α (CIFN), the first dosing regimen comprises administering CIFN at about 9 μg, about 15 μg, about 18 μg, or about 27 μg. The first dosing regimen can encompass a single dosing event, or at least two or more dosing events. The first dosing regimen of the Type I or III interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
The first dosing regimen of the Type I or III interferon receptor agonist is administered for a first period of time, which time period can be at least about 4 weeks, at least about 8 weeks, or at least about 12 weeks.
The second dosing regimen of the Type I or III interferon receptor agonist (also referred to as “the maintenance dose”) generally involves administration of a lower amount of the Type I or III interferon receptor agonist. For example, in the case of CIFN, the second dosing regimen comprises administering CIFN at least about 3 μg, at least about 9 μg, at least about 15 μg, or at least about 18 μg. The second dosing regimen can encompass a single dosing event, or at least two or more dosing events.
The second dosing regimen of the Type I or III interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
In some embodiments, where an “induction“/“maintenance” dosing regimen of a Type I or a III interferon receptor agonist is administered, a “priming” dose of a Type II interferon receptor agonist is included. In these embodiments, Type II interferon receptor agonist can be administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or III interferon receptor agonist. This period of time is referred to as the “priming” phase. In some of these embodiments, Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or III interferon receptor agonist. In other embodiments, Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I or III interferon receptor agonist. In some of these embodiments, the total time of treatment with the Type II interferon receptor agonist (including the “priming” phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to about 18 days, or from about 12 days to about 16 days.
In other embodiments, the Type I or III interferon receptor agonist is administered in a non-induction (single) dosing regimen. For example, in the case of CIFN, the dose of CIFN is generally in a range of from about 3 μg to about 15 μg, or from about 9 μg to about 15 μg. The dose of Type I or a Type III interferon receptor agonist is generally administered daily, every other day, three times a week, every other week, three times per month, once monthly, or substantially continuously. The dose of the Type I or III interferon receptor agonist is administered for a period of time, which period can be, for example, from at least about 24 weeks to at least about 48 weeks, or longer.
In some embodiments, where a single dosing regimen of a Type I or III interferon receptor agonist is administered, a “priming” dose of Type II interferon receptor agonist is included. For example, a Type II interferon receptor agonist can be administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or III interferon receptor agonist. This period of time is referred to as the “priming” phase. In some of these embodiments, Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or III interferon receptor agonist. In other embodiments, Type II interferon receptor agonist treatment is discontinued before the end of treatment with Type I or III interferon receptor agonist. In some of these embodiments, the total time of treatment with the Type II interferon receptor agonist (including the “priming” phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to about 18 days, or from about 12 days to about 16 days. Type II interferon receptor agonist
In some embodiments, the Type II interferon receptor agonist is an IFN-γ. Effective dosages of IFN-γ can range from about 0.5 μg/m2 to about 500 μg/m2, usually from about 1.5 μg/m2 to 200 μg/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 μg of protein. IFN-γ can be administered daily, every other day, three times a week, or substantially continuously or continuously.
In specific embodiments of interest, IFN-γ is administered to an individual in a unit dosage form of from about 25 μg to about 500 μg, from about 50 μg to about 400 μg, or from about 100 μg to about 300 μg. In particular embodiments of interest, the dose is about 200 μg IFN-γ. In many embodiments of interest, IFN-γ1b is administered.
Where the dosage is 200 μg IFN-γ per dose, the amount of IFN-γ per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 μg IFN-γ per kg body weight to about 1.48 μg IFN-γ per kg body weight.
The body surface area of subject individuals generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-γ dosage ranges from about 150 μg/m2 to about 20 μg/m2. For example, an IFN-γ dosage ranges from about 20 μg/m2 to about 30 μg/m2, from about 30 μg/m2 to about 40 μg/m2, from about 40 μg/m2 to about 50 μg/m2, from about 50 μg/m2 to about 60 μg/m2, from about 60 μg/m2 to about 70 μg/m2, from about 70 μg/m2 to about 80 μg/m2, from about 80 μg/m2 to about 90 μg/m2, from about 90 μg/m2 to about 100 μg/m2, from about 100 μg/m2 to about 110 μg/m2, from about 110 μg/m2 to about 120 μg/m2, from about 120 μg/m2 to about 130 μg/m2, from about 130 μg/m2 to about 140 μg/m2, or from about 140 μg/m2 to about 150 μg/m2. In some embodiments, the dosage groups range from about 25 μg/m2 to about 100 μg/m2. In other embodiments, the dosage groups range from about 25 μg/m2 to about 50 μg/m2.
TNF Antagonist
Effective dosages of a TNF-α antagonist range from 0.1 μg to 40 mg per dose, e.g., from about 0.1 μg to about 0.5 μg per dose, from about 0.5 μg to about 1.0 μg per dose, from about 1.0 μg per dose to about 5.0 μg per dose, from about 5.0 μg to about 10 μg per dose, from about 10 μg to about 20 μg per dose, from about 20 μg per dose to about 30 μg per dose, from about 30 μg per dose to about 40 μg per dose, from about 40 μg per dose to about 50 μg per dose, from about 50 μg per dose to about 60 μg per dose, from about 60 μg per dose to about 70 μg per dose, from about 70 μg to about 80 μg per dose, from about 80 μg per dose to about 100 μg per dose, from about 100 μg to about 150 μg per dose, from about 150 μg to about 200 μg per dose, from about 200 μg per dose to about 250 μg per dose, from about 250 μg to about 300 μg per dose, from about 300 μg to about 400 μg per dose, from about 400 μg to about 500 μg per dose, from about 500 μg to about 600 μg per dose, from about 600 μg to about 700 μg per dose, from about 700 μg to about 800 μg per dose, from about 800 μg to about 900 μg per dose, from about 900 μg to about 1000 μg per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.
In some embodiments, the TNF-α antagonist is EMBREL® etanercept. Effective dosages of etanercept range from about 0.1 μg to about 40 mg per dose, from about 0.1 μg to about 1 μg per dose, from about 1 μg to about 10 μg per dose, from about 10 μg to about 100 μg per dose, from about 100 μg to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.
In some embodiments, effective dosages of a TNF-α antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-α antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e.g., from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.
In some embodiments, the TNF-α antagonist is REMICADE® infliximab. Effective dosages of REMICADE® range from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, from about 4.0 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/kg to about 10 mg/kg per dose.
In some embodiments the TNF-α antagonist is HUMIRA™ adalimumab. Effective dosages of HUMIRA™ range from about 0.1 μg to about 35 mg, from about 0.1 μg to about 1 μg, from about 1 μg to about 10 μg, from about 10 μg to about 100 μg, from about 100 μg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.
In many embodiments, a TNF-α antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-α antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.
In many embodiments, multiple doses of a TNF-α antagonist are administered. For example, a TNF-α antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.
Pirfenidone or a Pirfenidone Analog
Pirfenidone or a pirfenidone analog can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
Effective dosages of pirfenidone or a specific pirfenidone analog include a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use are described in U.S. Pat. Nos., 5,310,562; 5,518,729; 5,716,632; and 6,090,822.
Thyrnosin-α
Thymosin-α (Zadaxin™) is generally administered by subcutaneous injection. Thymosin-α can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously. In many embodiments, thymosin-α is administered twice per week.
Effective dosages of thymosin-α range from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about 2.5 mg to about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from about 4.0 mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg. In particular embodiments, thymosin-α is administered in dosages containing an amount of 1.0 mg or 1.6 mg.
Thymosin-α can be administered over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
Ribavirin, Levovirin, Viramidine
Ribavirin is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 μm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day. In some embodiments, ribavirin is administered orally in dosages of about 400, about 800, about 1000, or about 1200 mg per day.
Levovirin is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 μm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day. In some embodiments, levovirin is administered orally in dosages of about 400, about 800, about 1000, or about 1200 mg per day.
Viramidine is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 μm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day. In some embodiments, viramidine is administered orally in dosages of about 800, or about 1600 mg per day.
In many embodiments, multiple doses of a ribavirin, levovirin, viramidine, isatoribine, and/or other nucleoside analogs are administered. For example, a nucleoside analog is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
NS3 Inhibitors, NS5B Inhibitors
Effective dosages of an HCV enzyme inhibitor range from about 10 mg to about 200 mg per dose, e.g., from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, from about 35 mg to about 40 mg per dose, from about 40 mg per dose to about 45 mg per dose, from about 45 mg per dose to about 50 mg per dose, from about 50 mg per dose to about 60 mg per dose, from about 60 mg per dose to about 70 mg per dose, from about 70 mg per dose to about 80 mg per dose, from about 80 mg per dose to about 90 mg per dose, from about 90 mg per dose to about 100 mg per dose, from about 100 mg per dose to about 125 mg per dose, from about 125 mg per dose to about 150 mg per dose, from about 150 mg per dose to about 175 mg per dose, or from about 175 mg per dose to about 200 mg per dose.
In some embodiments, effective dosages of an HCV enzyme inhibitor are expressed as mg/kg body weight. In these embodiments, effective dosages of an HCV enzyme inhibitor are from about 0.01 mg/kg body weight to about 100 mg/kg body weight, from about 0.I mg/kg body weight to about 50 mg/kg body weight, from about 0.1 mg/kg body weight to about 1 mg/kg body weight, from about 1 mg/kg body weight to about 10 mg/kg body weigh, from about 10 mg/kg body weight to about 100 mg/kg body weight, from about 5 mg/kg body weight to about 400 mg/kg body weight, from about 5 mg/kg body weight to about 50 mg/kg body weight, from about 50 mg/kg body weight to about 100 mg/kg body weight, from about 100 mg/kg body weight to about 200 mg/kg body weight, from about 200 mg/kg body weight to about 300 mg/kg body weight, or from about 300 mg/kg body weight to about 400 mg/kg body weight.
In many embodiments, an HCV enzyme inhibitor is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The HCV enzyme inhibitor can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.
In many embodiments, multiple doses of an HCV enzyme inhibitor are administered. For example, an HCV enzyme inhibitor is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
Side Effect Management Agent
Any subject monotherapy or combination therapy can be modified to include administration of a side effect management agent. Side effects of Type I interferon receptor agonist treatment include, but are not limited to, fever, malaise, tachycardia, chills, headache, arthralgia, myalgia, myelosuppression, suicide ideation, platelet suppression, neutropenia, lymphocytopenia, erythrocytopenia (anemia), and anorexia. In some embodiments, an effective amount of a palliative agent reduces a side effect induced by treatment with a Type I interferon receptor agonist by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or more, compared to the rate of occurrence or the degree or extent of the side effect when the Type I interferon receptor agonist is administered without the palliative agent. For example, if a fever is experienced with the Type I interferon receptor agonist therapy, then the body temperature of an individual treated with the Type I interferon receptor agonist therapy and palliative agent according to the instant invention is reduced by at least 0.5 degree Fahrenheit, and in some embodiments is within the normal range, e.g., at or near 98.6° F.
Side effects of pirfenidone or a pirfenidone analog include gastrointestinal disturbances and discomfort. Gastrointestinal disturbances include nausea, diarrhea, gastrointestinal cramping, and the like. In some embodiments, an effective amount of a palliative agent reduces a side effect induced by treatment with a pirfenidone or a pirfenidone analog by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or more, compared to the rate of occurrence or the degree or extent of the side effect when the pirfenidone or pirfenidone analog is administered without the palliative agent.
Side effects of other, additional therapeutic agents (e.g., anti-angiogenic agents; anti-cancer agents such as anti-proliferative agents, anti-neoplastic agents, and cytotoxic agents; anti-fibrotic agents; TNF-α antagonists; and anti-inflammatory agents) are well known. For example, side effects of anti-neoplastic agents include gastrointestinal discomfort. Other side effects of additional therapeutic agents include fever, malaise, etc.
Combination Regimens for Treating a Hepatitis C Virus Infection
The present invention provides methods of treating HCV infection by administering a combination of a Type I or III interferon receptor agonist, an immunomodulatory agent, and an HCV enzyme inhibitor in a therapeutically effective amount to an individual in need thereof. In some embodiments, the Type I interferon receptor agonist is IFN-α. Immunomodulatory agents can be selected from i) a Type II interferon receptor agonist; ii) a TNF antagonist; iii) pirfenidone or a pirfenidone analog; iv) and thymosin-α. Where the immunomodulatory agent is a Type II interferon receptor agonist, in many embodiments the Type II interferon receptor agonist is IFN-γ. HCV enzyme inhibitors are selected from NS3 protease inhibitors; NS3 lielicase inhibitors; and NS5B RNA-dependent RNA polymerase inhibitors. IFN-α, IFN-γ, and HCVenzyine inhibitor in combination therapy
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of an IFN-α selected from (i) INFERGEN( containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, or per day continuously or substantially continuously; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per Idlogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per Idlogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGASYS® peginterferon alfa-2a containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEG-INTRON® peginterferon alfa-2b containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of mono PEG(30 kd, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear.)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or once monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON®D containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per lilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of IFN-α2 containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c, subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGASYS® peginterferon alfa-2a containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEG-INTRON® peginterferon alfa-2b containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or once monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; and d) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; and d) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; and d) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 1 0 MU of drug per dose of IFN-α2a, 2b or 2c, subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; and d) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGASYS® peginterferon alfa-2a containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; and d) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEG-INTRON® peginterferon alfa-2b containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; and d) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or once monthly; b) a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.0 1 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; and d) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 1 00 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
Any of the above-described regimens involving administration of IFN-α, IFN-γ, and an NS3 protease inhibitor; IFN-α, IFN-γ, and an NS5B RNA-dependent RNA polymerase inhibitor; or IFN-α, IFN-γ, an NS3 protease inhibitor and an NS5B RNA-dependent RNA polymerase inhibitor, can be modified to further comprise administering an effective amount of an additional antiviral agent. In some embodiments, a subject combination therapy method for treating an HCV infection in an individual comprises co-administering effective amounts of IFN-α, IFN-γ, an NS3 protease inhibitor, and a second immunomodulatory, agent. In other embodiments, a subject combination therapy method for treating an HCV infection in an individual comprises co-administering effective amounts of IFN-α, IFN-γ, an NS5B RNA-dependent RNA polymerase inhibitor, and a second immunomodulatory agent. In other embodiments, a subject combination therapy method for treating an HCV infection in an individual comprises co-administering effective amounts of IFN-α, IFN-γ, an NS3 protease inhibitor, an NS5B RNA-dependent RNA polymerase inhibitor, and a second immunomodulatory agent.
As non-limiting examples, any of the above-described IFN-α, IFN-γ and HCV enzyme inhibitor combination regimens can be modified to include: (a) administering a dosage of a TNF-A antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; (b) administering a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; or (c) administering a dosage of Zadaxin™ thymosin-α containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration. IFN-α, TNF antagonist, and HCV enzyme inhibitor in combination therapy
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD), linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per idlogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of a TNF-A antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c, subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 1 0 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.0 1 mg to about 1 00 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.0 1 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE®D in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of a TNF-A antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of a TNF-A antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 1 0 MU of drug per dose of IFN-α2a, 2b or 2c, subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE®D in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 1 00 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON®M containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 46 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c, subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
Any of the above-described regimens involving administration of IFN-α, a TNF antagonist, and an NS3 protease inhibitor; IFN-α, a TNF antagonist, and an NS5B RNA-dependent RNA polymerase inhibitor; or IFN-α, a TNF antagonist, an NS3 protease inhibitor and an NS5B RNA-dependent RNA polymerase inhibitor, can be modified to further comprise administering an effective amount of an additional immunomodulatory agent. Thus, in some embodiments, a subject combination therapy method for treating an HCV infection in an individual comprises co-administering effective amounts of IFN-α, a TNF antagonist, an NS3 protease inhibitor, and a second immunomodulatory agent. In other embodiments, a subject combination therapy method for treating an HCV infection in an individual comprises co-administering effective amounts of IFN-α, a TNF antagonist, an NS5B RNA-dependent RNA polymerase inhibitor, and a second immunomodulatory agent. In other embodiments, a subject combination therapy method for treating an HCV infection in an individual comprises co-administering effective amounts of IFN-α, a TNF antagonist, an NS3 protease inhibitor, an NS5B RNA-dependent RNA polymerase inhibitor, and a second immunomodulatory agent.
As non-limiting examples, any of the above-described IFN-α, TNF antagonist and HCV enzyme inhibitor combination regimens can be modified to include: (a) administering a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; (b) administering a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; (c) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; (d) a dosage of ribavirin or a derivative thereof, in an amount of about 400 mg, 800 mg, 1000 mg, or 1200 mg orally daily for the desired treatment duration; (e) a dosage of levovirin, in an amount of about 400 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg orally daily for the desired treatment duration; or (f) a dosage of Viramidine™ in an amount of from about 800 mg to about 1600 mg orally daily for the desired treatment duration.
IFN-α, Pirfenidone or a Pirfenidone Analog, and an HCV Enzyme Inhibitor in Combination Therapy
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 1kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c, subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 1kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c, subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c, subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per ldlogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
Any of the above-described regimens involving administration of IFN-α, pirfenidone or a pirfenidone analog, and an NS3 protease inhibitor; IFN-α, pirfenidone or a pirfenidone analog, and an NS5B RNA-dependent RNA polymerase inhibitor; or IFN-α, pirfenidone or a pirfenidone analog, an NS3 protease inhibitor and an NS5B RNA-dependent RNA polymerase inhibitor, can be modified to further comprise administering an effective amount of an additional immunomodulatory agent. Thus, in some embodiments, a subject combination therapy method for treating an HCV infection in an individual comprises co-administering effective amounts of IFN-α, pirfenidone or a pirfenidone analog, an NS3 protease inhibitor, and a second immunomodulatory agent. In other embodiments, a subject combination therapy method for treating an HCV infection in an individual comprises co-administering effective amounts of IFN-α, pirfenidone or a pirfenidone analog, an NS5B RNA-dependent RNA polymerase inhibitor, and a second immunomodulatory agent. In other embodiments, a subject combination therapy method for treating an HCV infection in an individual comprises co-administering effective amounts of IFN-α, pirfenidone or a pirfenidone analog, an NS3 protease inhibitor, an NS5B RNA-dependent RNA polymerase inhibitor, and a second immunomodulatory agent.
As non-limiting examples, any of the above-described IFN-α, pirfenidone or pirfenidone analog, and HCV enzyme inhibitor combination regimens can be modified to include: (a) administering a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; (b) administering a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; (c) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; (d) a dosage of ribavirin or a derivative thereof, in an amount of about 400 mg, 800 mg, 1000 mg, or 1200 mg orally daily for the desired treatment duration; (e) a dosage of levovirin, in an amount of about 400 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg orally daily for the desired treatment duration; or (f) a dosage of Viramidine™ in an amount of from about 800 mg to about 1600 mg orally daily for the desired treatment duration.
IFN-α, Thymosin-α, and an HCV Enzyme Inhibitor in Combination Therapy
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 1000 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c, subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.0 1 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c, subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; and c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every . 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.0 1 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per ldlogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of IFN-α2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α2a, 2b or 2c, subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type I interferon receptor agonist, ii) an immunomodulatory agent; and iii) an HCV enzyme inhibitor in the treatment of an HCV infection in a patient, comprising co-administering to the patient a) a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration; b) a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration; c) a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to achieve a sustained viral response.
Any of the above-described regimens involving administration of: (1) IFN-α, thymosin-α, and an NS3 protease inhibitor; (2) IFN-α, thymosin-α, and an NS5B RNA-dependent RNA polymerase inhibitor; or (3) IFN-α, thymosin-α, an NS3 protease inhibitor and an NS5B RNA-dependent RNA polymerase inhibitor; can be modified to further comprise administering an effective amount of an additional antiviral agent. Thus, in some embodiments, a subject combination therapy method for treating an HCV infection in an individual comprises co-administering effective amounts of IFN-α, thymosin-α, an NS3 protease inhibitor, and a second immunomodulatory agent. In other embodiments, a subject combination therapy method for treating an HCV infection in an individual comprises co-administering effective amounts of IFN-α, thymosin-α, an NS5B RNA-dependent RNA polymerase inhibitor, and a second immunomodulatory agent. In other embodiments, a subject combination therapy method for treating an HCV infection in an individual comprises co-administering effective amounts of IFN-α, thymosin-α, an NS3 protease inhibitor, an NS5B RNA-dependent RNA polymerase inhibitor, and a second immunomodulatory agent.
As non-limiting examples, any of the above-described IFN-α, thymosin-α, and HCV enzyme inhibitor combination regimens can be modified to include: (a) administering a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously; (b) administering a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; (c) administering a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; (d) administering a dosage of ribavirin or a derivative thereof, in an amount of about 400 mg, 800 mg, 1000 mg, or 1200 mg orally daily for the desired treatment duration; (e) administering a dosage of levovirin, in an amount of about 400 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg orally daily for the desired treatment duration; or (f) administering a dosage of viramidine in an amount of from about 800 mg to about 1600 mg orally daily for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α regimen can be modified to replace the subject IFN-α regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α regimen can be modified to replace the subject IFN-α regimen with a regimen of INFERGEN® interferon alfacon-1 comprising administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily or three times per week for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α regimen can be modified to replace the subject IFN-α regimen with a regimen of INFERGEN® interferon alfacon-1 comprising administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily or three times per week for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-γ regimen can be modified to replace the subject IFN-γ regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-γ regimen can be modified to replace the subject IFN-γ regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γcombination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring a TNF antagonist regimen can be modified to replace the subject TNF antagonist regimen with a TNF antagonist regimen comprising administering a dosage of a TNF antagonist selected from the group of: (a) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (b) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (c) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ, combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α, and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN(M interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and IFN-γ combination regimen can be modified to replace the subject IFN-α and IFN-γ combination regimen with an IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) ilifliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and TNF antagonist combination regimen with an IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and TNF antagonist combination regimen can be modified to replace the subject IFN-α and TNF antagonist combination regimen with an IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-αcontaining an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and TNF antagonist combination regimen can be modified to replace the subject IFN-α and TNF antagonist combination regimen with an IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and TNF antagonist combination regimen can be modified to replace the subject IFN-α and TNF antagonist combination regimen with an IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN(I interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily or three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-α and TNF antagonist combination regimen can be modified to replace the subject IFN-α and TNF antagonist combination regimen with an IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily or three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-γ and TNF antagonist combination regimen with an IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-γ and TNF antagonist combination regimen with an IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 180 μg of drug per dose, subcutaneously once weekly for the desired treatment duration.
As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 1.0 μg of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration.
As non-limiting examples, any of the above-described methods can be modified to include administering a dosage of ribavirin containing an amount of 400 mg, 800 mg, 1000 mg or 1200 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.
As non-limiting examples, any of the above-described methods can be modified to include administering a dosage of ribavirin containing (i) an amount of 1000 mg of drug orally per day for patients having a body weight of less than 75 kg or (ii) an amount of 1200 mg of drug orally per day for patients having a body weight of greater than or equal to 75 kg, optionally in two or more divided doses per day, for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an HCV NS3 inhibitor regimen can be modified to replace the subject HCV NS3 inhibitor regimen with an HCV NS3 inhibitor regimen comprising administering a dosage of 0.01 mg to 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an HCV NS3 inhibitor regimen can be modified to replace the subject HCV NS3 inhibitor regimen with an HCV NS3 inhibitor regimen comprising administering a dosage of 0.1 mg to 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an HCV NS3 inhibitor regimen can be modified to replace the subject HCV NS3 inhibitor regimen with an HCV NS3 inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an HCV NS3 inhibitor regimen can be modified to replace the subject HCV NS3 inhibitor regimen with an HCV NS3 inhibitor regimen comprising administering a dosage of 10 mg to 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an HCV NS5B inhibitor regimen can be modified to replace the subject HCV NS5B inhibitor regimen with an HCV NS5B inhibitor regimen comprising administering a dosage of 0.01 mg to 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an HCV NS5B inhibitor regimen can be modified to replace the subject HCV NS5B inhibitor regimen with an HCV NS5B inhibitor regimen comprising administering a dosage of 0.1 mg to 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an HCV NS5B inhibitor regimen can be modified to replace the subject HCV NS5B inhibitor regimen with an HCV NS5B inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.
As non-limiting examples, any of the above-described methods featuring an HCV NS5B inhibitor regimen can be modified to replace the subject HCV NS5B inhibitor regimen with an HCV NS5B inhibitor regimen comprising administering a dosage of 10 mg to 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.
Patient Identification
In certain embodiments, the specific regimen of drug therapy used in treatment of the HCV patient is selected according to certain disease parameters exhibited by the patient, such as the initial viral load, genotype of the HCV infection in the patient, liver histology and/or stage of liver fibrosis in the patient.
Thus, in some embodiments, the present invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a treatment failure patient for a duration of 48 weeks.
In other embodiments, the invention provides any of the above-described methods for HCV in which the subject method is modified to treat a non-responder patient, where the patient receives a 48 week course of therapy.
In other embodiments, the invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a relapser patient, where the patient receives a 48 week course of therapy.
In other embodiments, the invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a naive patient infected with HCV genotype 1, where the patient receives a 48 week course of therapy.
In other embodiments, the invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a naive patient infected with HCV genotype 1, where the patient has a high viral load (HVL), where “HVL” refers to an HCV viral load of greater than 2×106 HCV genome copies per mL serum, and where the patient receives a 48 week course of therapy.
In one embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.
In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.
In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and no or early stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and no or early stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.
In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks.
In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 24 weeks.
In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks.
In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 24 weeks.
In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of at least about 24 weeks.
In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of HCV genotypes 5, 6, 7, 8 and 9 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks.
In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of HCV genotypes 5, 6, 7, 8 and 9 and then (2) administering to the patient the drug therapy of the subject method for a time period of at least about 24 weeks and up to about 48 weeks.
Subjects Suitable for Treatment
Individuals who are to be treated according to the methods of the invention include individuals who have been clinically diagnosed as infected with HCV. Individuals who are infected with HCV are identified as having HCV RNA in their blood, and/or having anti-HCV antibody in their serum.
Individuals who are clinically diagnosed as infected with HCV include naive individuals (e.g., individuals not previously treated for HCV, particularly those who have not previously received IFN-α-based and/or ribavirin-based therapy) and individuals who have failed prior treatment for HCV (“treatment failure” patients). Treatment failure patients include non-responders (i.e., individuals in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV, e.g., a previous IFN-α monotherapy, a previous IFN-α and ribavirin combination therapy, or a previous pegylated IFN-α and ribavirin combination therapy); and relapsers (i.e., individuals who were previously treated for HCV, e.g., who received a previous IFN-α monotherapy, a previous IFN-α and ribavirin combination therapy, or a previous pegylated IFN-α and ribavirin combination therapy, whose HCV titer decreased, and subsequently increased).
In particular embodiments of interest, individuals have an HCV titer of at least about 105, at least about 5×105, or at least about 106, or at least about 2×106, genome copies of HCV per milliliter of serum. The patient may be infected with any HCV genotype (genotype 1, including 1a and 1b, 2, 3, 4, 6, etc. and subtypes (e.g., 2a, 2b, 3a, etc.)), particularly a difficult to treat genotype such as HCV genotype 1 and particular HCV subtypes and quasispecies.
Also of interest are HCV-positive individuals (as described above) who exhibit severe fibrosis or early cirrhosis (non-decompensated, Child's-Pugh class A or less), or more advanced cirrhosis (decompensated, Child's-Pugh class B or C) due to chronic HCV infection and who are viremic despite prior anti-viral treatment with IFN-α-based therapies or who cannot tolerate IFN-α-based therapies, or who have a contraindication to such therapies. In particular embodiments of interest, HCV-positive individuals with stage 3 or 4 liver fibrosis according to the METAVIR scoring system are suitable for treatment with the methods of the present invention. In other embodiments, individuals suitable for treatment with the methods of the instant invention are patients with decompensated cirrhosis with clinical manifestations, including patients with far-advanced liver cirrhosis, including those awaiting liver transplantation. In still other embodiments, individuals suitable for treatment with the methods of the instant invention include patients with milder degrees of fibrosis including those with early fibrosis (stages 1 and 2 in the METAVIR, Ludwig, and Scheuer scoring systems; or stages 1, 2, or 3 in the Ishak scoring system.).
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.
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Music - Jazz Studies Option, B.A.
Bachelor of Arts Degree Requirements
Each student seeking a Bachelor of Arts degree with a major in music must fulfill the Basic Core Requirements and all requirements listed under the music degree option which is the student's major field of study. Students must also fulfill the university's General Education requirements (49 units), including remaining music degree requirements (e.g. it is strongly recommended that vocal performance majors pass two semesters of university-level foreign language study in either French, German, or Italian) and Other Departmental Requirements to complete the B.A. (minimum 120 units). Each music major must consult with a designated music faculty advisor each semester before they may enroll in music classes.
Please note: Entrance examinations in music theory and aural skills and auditions in the declared performing medium are required of all freshmen and transfer music majors. Admission to the B.A. in Music is contingent upon audition and availability. Detailed information regarding entrance and degree requirements is available in the Department of Music Undergraduate Student Handbook.
1. Major requirements (69 units)
Core (28 units)
(required of all music majors regardless of option)
MUSIC 1A, 1B, 1C, 1D, 40, 41, 42, 43, 58, 161A, 161B (24 units)
MUSIC 4B, 4C [Keyboard students: MUSIC 14 and 114] (see note 1) (4 units)
MUSIC 20 - Convocation (8 semesters) (0 units)
Options (41 units)
I. Music as a Liberal Art (41 units)
II. Music Education (41 units)
III. Instrumental Performance (41 units)
IV. Vocal Performance (41 units)
V. Composition (41 units)
VI. Jazz Studies (41 units)
Additional requirements (9 units)
Music majors must take the following courses, which also satisfy 9 units of General Education requirements: BREADTH (Area C1) MUSIC 9A and MUSIC 74; INTEGRATION (Area IC) MUSIC 171
2. General Education requirement (49 units)
5.Total (120 units)*
* G.E. and MI courses can be double-counted with major requirements. The writing requirement may be met by taking the upper-division writing exam. See advisor for details.
Degree Option
VI. Jazz Studies
MUSIC 31 through MUSIC 38 (2 units)
MUSIC 131J through MUSIC 135J (must complete Jury II in jazz by the end of the second unit) (6 units)
MUSIC 162 (2 units)
Four semesters in MUSIC 103 (4 units)
Four semesters in MUSIC 103JO or 102JE (4 units)
MUSIC 117JC (2 units)
Other music electives (with advisor's approval) (7 units)
MUSIC 198 (Senior Recital) (2 units)
Music students must pass a piano proficiency examination after completion of MUSIC 4C. Passing MUSIC 4C does not constitute passing the proficiency exam. MUSIC 4B and 4C may be waived by passing the designated Piano Proficiency Exam. Pianists must substitute MUSIC 14 and 114 for Music 4B and 4C. Successful completion of MUSIC 14 and 114 satisfies piano proficiency requirement for piano students. (See Department of Music Undergraduate Student Handbook for details. Students for whom any of these courses are waived should fulfill the minimum unit requirements with elective courses.)
See Other Departmental Requirements.
Advanced standing designation is granted after passing Jury II.
Other Departmental Requirements
Undergraduate music majors must select a degree option from the following: Music as a Liberal Art; Music Education: Choral, General or Instrumental Emphasis; Instrumental Performance; Vocal Performance; Composition; or Jazz Studies. Note: All students majoring in music are automatically enrolled in Music as a Liberal Art until they have been officially admitted to another degree option. All entering students (freshmen and transfer) must take a diagnostic examination in music theory. Other degree options have audition or other admission requirements which must be fulfilled before a student is officially recognized as enrolled in that option.
Music education and performance degree options require students to declare a primary concentration (e.g. an instrument or voice).
Upon conclusion of the second semester of MUSIC 31-39, 48 or 110, students must attempt Jury I in their declared area of concentration before being permitted to continue their major. Students are allowed two attempts, taken in consecutive semesters, to pass Jury I.
Students majoring in music must enroll in a piano class (MUSIC 9A, 4B, and 4C) until the departmental piano proficiency examination has been passed. (See Department of Music Undergraduate Student Handbook for details.)
Passing of the piano proficiency examination and successful completion of MUSIC 1B are required before attempting Jury II.
Jury II must be passed for advanced standing for students enrolled in the Music Education, Vocal Performance, Instrumental Performance, and Composition options. Jury II is not required of students enrolled in the Music as a Liberal Art Option. Students are allowed two attempts, taken in consecutive semesters, to pass Jury II. Failure to pass a second attempt will result in the student being dropped from the Music Education, Vocal Performance, Instrumental Performance, Jazz Studies, and Composition options. These students may continue the major in the Music as a Liberal Art option.
Guitar and piano students will fulfill 50 percent of the major ensemble requirement by enrolling in Guitar Ensemble, Keyboard Ensemble, Chamber Music Ensemble, Music Accompanying, or MUSIC 130T (as specified by their studio instructor). The remaining 50 percent must be fulfilled by enrolling in either Symphony Orchestra, Wind Orchestra, Symphonic Band, Jazz Orchestra, Concert Choir, or Marching Band.
Music Education Option students must pass a conducting proficiency examination after completion of MUSIC 158. Passing MUSIC 158 does not constitute passing the proficiency examination.
Students in MUSIC 31 and 131 through 39 and 139 (private studio instruction) will perform in student recitals when assigned by their instructor.
Guitar and piano students will fulfill 50 percent of the major ensemble requirement by enrolling in Guitar Ensemble, Keyboard Ensemble, Chamber Music Ensemble, Music Accompanying, or MUSIC 130T (as specified by their studio instructor). The remaining 50 percent must be fulfilled by enrolling in either Orchestra, Wind Ensemble, Symphonic Band, Concert Choir, or Marching Band.
Music students must earn a grade of C or better in each course used to satisfy the requirements of the major, including the core and specific option. No course taken for the music major can be graded on a CR/NC basis except for courses with mandatory CR/NC grading.
Vocal performance majors must take two consecutive semesters of the same foreign language approved by the vocal instructor. One course can be used for G.E. credit where applicable.
The Department of Music faculty has backgrounds in varied areas of specialization. Many members of the faculty have national and international reputations as performing artists and teachers. Others are well known for their scholarly research, articles, and books. They are all dedicated to providing students with the best music education possible both in their classes and studios.
B.A. in Music - Jazz Studies
The Department of Music provides undergraduate instruction in music for those planning professional careers as performers, composers, and studio teachers, as well as those preparing for advanced degrees in performance and composition. It also provides State-approved subject matter preparation required for a California teaching credential in music, and graduate instruction for students planning professional and academic careers or seeking professional growth as K-12 teachers or junior college instructors. Students can also acquire a broad acquaintance with music for the community and non music major.
The new 65,000 square foot Music Building, combined with an extensive remodeling of the existing facility ensures that students enjoy all the advantages possible in a modern facility. The building houses the 320 seat Concert Hall, the 100 seat Whalberg Recital Hall, a 220 seat Rehearsal Hall, as well as over 30 practice rooms, classrooms, a large dance studio, faculty office space, a conference room, and 700 student lockers. The building also contains two digital recording studios, computer labs, MIDI and electronic music labs, and a tracker-action organ.
Public School Teacher
Source: HR Reported data from salary.com as of December 2012
Music Directors and Composers
$45,090 (mean annual wage)
Source: Bureau of Labor Statistics, bls.gov
Full-Time Church Music Director
Associate Professor - Music
Music Performer or Composer
Music Sales Representative
Instrument Technician
Recording Technician
Artist Representative
Church Music Director
Major Ensembles (concert choir, jazz orchestra, marching band symphony orchestra, symphonic band, and wind orchestra)
Minor Ensembles (chamber singers, flute ensemble, guitar ensemble, jazz ensemble, men's chorus, contemporary music ensemble, basketball pep band, percussion ensemble, string ensemble, women's chorus, and woodwind ensembles)
Specialty Ensembles: Bulldog Beat, Clendenin Brass Quintet, Chamber Music, Keyboard Ensemble, Mariachi, and President's Quintet (Woodwind)
Flamenco Guitar Interpretation
Introduction to Music Technology
Jazz Theory and Improvisation
Pop Music: Jazz and Rock
Professional performing proficiency on an instrument or voice
Use of computer technology for composing, sequencing and recording
Ability to improvise in a variety of settings
Understanding of the way historical aspects of music relate to performance and style interpretation
Understanding of music from diverse cultures
Understanding of musicianship and theoretical aspects of music, including ear training, sight-singing, analysis and composition
The College of Arts and Humanities provides a diverse student population with the communication skills, humanistic values and cultural awareness that form the foundation of scholarship. The college offers intellectual and artistic programs that engage students and faculty and the community in collaboration, dialog and discovery. These programs help preserve, illuminate and nourish the arts and humanities for the campus and for the wider community.
College of Arts & Humanities
2380 E. Keats MS/MB99
email Dean's office
We are located in the west wing of the Music Building in Room 186.
Office Location: Music Building, Room 134
email Music Department
2380 E. Keats Avenue M/S MB77
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Archive for the 2007 Category
V/A- Adaptations From the Moon: Tuxedomooning the World
Posted in 2007, abstract, ambient, covers, darkwave, experimental, john costello, minimal, minimal synth, tuxedomoon, tuxedomooning on August 1, 2011 by Frankie Teardrop
Here’s a recent compilation sent my way by John Costello, a name that should already be familiar from previous posts. Here we have a CD release of Tuxedomoon interpretations from 2007, as recorded by several members of a prominent TM message board. This CD exists as a non-for-profit venture via the site Tuxedomooning.com and while it isn’t available for sale, though there may be some copies available for those wishing to market the disc.
Fans of Tuxedomoon should find a fair mix of selections from the band’s career, done with care and finesse by several prominent underground artists. Cult With No Name also appear here, and Costello contributes TWO tracks. Allow me to expand on this post with some info and behind the scenes from Costello himself:
“[The compilation] grew out of the TM yahoo group forum started by Erik Stein (he’s also half of lounge electro duo Cult With No Name). Amid the renewed hustle of TM activity, French label Optical Sound released a covers cd in 2006, Next To Nothing, with artists including Simon Fisher Turner and Scanner. Oliver Schupp (of German band Festspielhaus), proposed a forum members covers cd and, when he found enough takers, took it forward from there. It was sanctioned by TM as a not-for-profit venture of 300 cds, with copies bought by the contributors to distribute how they wished and the rest sold by Oliver to forum members or interested parties at cost until they ran out.
I agonised for a long time over which track to choose, as there were so many candidates. Right up to the last minute I was going to do “No Tears” but I finally chose “Everything You Want,” in a rawer rocked-up style closer to the live version on Ten Years In One Night than the early Subterranean Modern Ralph Records compilation album version.
I record with my good friend and producer Geoff Pinckney at his Alien 6 studio in Sussex. Geoff is in electro outift Tenek with Pete Steer, and ex-of Glasshouse who supported Gary Numan on a couple of tours in the late 80s/early 90s. My method of working is to record and mix each track in as close to a day as possible, but I gave EYW three to make sure it would pass muster – it’s quite daunting doing something as an amateur that will be a tribute to a band you’ve loved most of your life, and you want to do it right. The session went smoothly, unbelievably so in fact, and I finished in two days – so for the hell of it I decided to do another. I chose “Egypt” because I knew I could do a minimal version fast, and it took just six hours to record and mix. I tried to do both in the spirit of TM and worked in a few motifs from other tracks; also, the bass on “Egypt” is a sample of “The Waltz,” from Holy Wars. I had no idea if Oliver would find it surplus to requirements but he loved it and included it on the cd.
The reaction was very positive. The band issued congratulations on the forum for a job well done.”
Since there’s not much more I can add to that, let’s get to the info!
Various Artists- Adaptations From The Moon: Tuxedomooning The World
1. John Costello– Everything You Want
2. Phlitman & Kangaroo– Ninotchka
3. Festspielhaus– In The Name Of Talent (Italian Western 2)
4. Gosane– Where Interests Lie
5. Cabaret Of Complexity– Blind
6. John Costello– Egypt
7. Another– What Use?
8. !!– In The Name Of Terror (Iraqi Western 2)
9. Cult With No Name– Some Guise
10. Gosane– Everything You Want / The Stranger
11. Duke Sexton– East
12. Dry Monopole– Time To Lose
13. MistakeMistake– (Special Treatment For The) Family Man
14. Willem Schipper– The Unknown Fan
*download it here*
Thanks again to John Costello for all the info, wisdom, and of course, the music! Please support him and check out more of his recent work here!
Otherwise, August is looking to be a busy month for me, so I may be sparse as the month progresses. That said, I am still expecting some goodies to come my way over the next few weeks, so I will post them as I can! That said, if you need a fix faster than I can provide one, be sure to sift through the back archives or many of the excellent blogs linked to the right. Great things being posted around every corner!
Bush Tetras
Posted in 1980s, 1990s, 2007, bush tetras, funk, no-wave, nyc, post-punk on November 5, 2007 by Frankie Teardrop
Today’s band, Bush Tetras, formed in the heart of New York City soon after the initial wave of the punk rock explosion. A female fronted dance-groovin’ post-punk band led by vocalist Cynthia Sley and complete with jerky rhythms and dissonant guitars, Bush Tetras first hit the scene in 1980 with a series of singles and EPs. Lead guitarist Pat Place’s previous credits included co-founding James Chance’s no-wave outfit the Contortions.
The band would achieve initial club success for their ‘Too Many Creeps’ single, a roaring, fiery, and jagged tune that helped draw attention to the budding post-punk and no-wave movements. The band would tour relentlessly during their initial tenure, forming a kinship with The Clash and experimenting with more Afro-rhythms and Caribbean influences.
After recording three proper EPs (Too Many Creeps, Boom In the Night, and Rituals), the band split up in 1983 upon the release of a live cassette entitled Wild Things. A further compilation of the band’s material saw the light of day (albeit also on cassette) in 1989, and it wasn’t until 1995, a year before the initial lineup would reform, that the band saw their first proper cd release, a compilation entitled Boom in the Night, which would collect all their previous efforts. In 1996, the band would record a new record entitled Beauty Lies, picking back up briefly from where they left off. After another decade of inactivity, the band released a combination compilation/record this year, entitled Very Very Happy, which features a handful of new tracks and a series of re-recorded tunes from their past, updating these songs and recording them as they were meant to be heard. The band is currently active and playing shows in East USA, so catch them if you can!
For your listening pleasure (and with the blessing of the Bush Tetra’s promotions dept./label), I’ve uploaded a duo of Bush Tetras tracks: the first is the title track from their 1981 Boom In the Night EP and the second, the freshly re-recorded take on their initial breakthrough single, ‘Too Many Creeps’- plucked from 2007’s Very Very Happy.
download Bush Tetras- ‘Things That Go Boom in the Night’
download Bush Tetras- ‘Too Many Creeps (2007 version)’
and for your viewing pleasure…here’s the band performing ‘Too Many Creeps’ live during NYC’s Ladyfest*East festival in 2002.
To pick up some Bush Tetras material on CD, check out these links:
Roir Online
CD Baby dot com
Systems of Romance was created in mid-2007 to serve as a dumping grounds for all great things coldwave, minimal synth, post-punk, synthpunk, industrial, synthpop, and various other combinations of these styles. Feel free to make requests, noodle around, and discuss all you like...
Otherwise, this blog is dedicated to showcasing material that has long since been out of print. If you are aware of any of these items being readily available from the artist or label, or take issue with these tracks being uploaded, please let me know so I can amend the post or remove the links.
SOR on Facebook
Feed Url
A Romance of Dots and Dashes
A Viable Commercial
Aberrant Adherents
Amnesia (Radio)
Annie's Animal
Attchort
Augenmusik
Banned From the Empire
Bleeps & Boops
bx-59cppw
Cactus Mouth Informer
Capa Nostra Syndicate
Club EBM
Crispy Nuggets
Dark Records
Different Illusion
DJ Bynar
Dreams and Voices
Eine Keine Angst Musik
Electronick Tapes
Fantasmi Macchina
Fantod Under Glass
Girls From Tahiti
Habit of Sex
Irk the Purists
Italo-Wave
Kakophonia
Kentucky Fried Wave
Last Days of Man On Earth
Med Denna Verkliga Kniv…
Nightmares on Wax
No Not Nyet
O Babylon
Raiding the Vinyl Archive
Redchapterjubilee Music Research
Return to the East
Shades of an Audio Daydream
Soundhead
Stalking Duppi
Symphony of Ghosts
Ten Thousand Eyes
The Forgotten Orchard
The Mongoose
The Same Mistakes
Totally Wired
Venus+On
Wifully Obscure
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BC Conservatives in the race?
A mysterious poll from the Mustel Group, mentioned in several different news articles but the only proof of its existence is here in this political tracking chart produced by the polling firm, shows that the BC Liberals and BC New Democrats continue to run neck-and-neck in the province. But it also shows that the BC Conservatives under newly minted leader John Cummins, a former MP for the federal Tories, are riding high at 18% support - up from their 2% in the 2009 provincial election.
UPDATE: Mustel has informed me the poll was taken between May 4-15 and included 500 respondents, meaning a margin of error of 4.4%, 19 times out of 20.
What can we make of this rise of the BC Conservatives? Certainly Cummins gives the party a good degree of legitimacy, and the more centrist Christy Clark might be pushing some voters further to the right. That there might be some confusion between the provincial and federal parties, or an undeserved transfer of support from one to the other in the wake of Stephen Harper's victory, could also be a major factor.
Compared to Mustel's last poll, this is an 11-point jump for the BC Conservatives, so nothing to sneeze at. This has hurt the BC Liberals, who are down four points from that December poll to 37%. The BC New Democrats are only down one point to 35%, indicating that they may be skating above the fray between the two provincial parties on the right. The Greens muddy the water, though, as they are down six points. A lot of support swapping seems to be going on.
Do the BC Conservatives need to be taken seriously? We cannot know if they will even run a full slate in the next provincial election. They were far from doing so in 2009. This also makes it a bit trickier to make seat projections. Until we know differently, I can only assume that the BC Conservatives will run candidates in the same ridings they did in 2009, which makes their prospects for seat gains much lower (that 18% is spread across the province, including the 2/3rds of ridings in which they did not run a candidate last time).
Accordingly, with this poll ThreeHundredEight projects the BC Conservatives win only one seat, Boundary - Similkameen. Of course, we don't know if they will even have a candidate there in the next election, as that could be as far away as 2013. And if they run a full slate, it is very difficult to predict which ridings might turn blue, and which ridings might go with the NDP because of a split between the Conservatives and the Liberals.
In any case, with this poll the BC Liberals win 46 seats, the BC New Democrats 37, and one independent is elected. A majority for Ms. Clark.
Still, it is a majority won within the margin of error. A two-point lead in a poll with a 4.4 margin of error is no lead at all, and certainly not something Ms. Clark could risk her majority government on. With the BC Conservatives coming from the right and the BC New Democrats not going anywhere, the prospects for an election in British Columbia this year would appear slim. But people have a way of doing funny things.
Posted by Éric at 11:43:00 AM
Labels: 40th British Columbian General Election, Mustel Group
Bernard 03 June, 2011 13:43
The BC Conservatives are planning on running a full slate in the next election and they have about 40-50 organized riding associations at the moment.
Trying to project the results for the Conservatives in the next election based on the last one is not realistic for a host of reasons. The Boundary Similkameen result was an aberration because the candidate for the Conservatives had been the Liberal candidate but dumped by the party.
With 18% and the nature of the way BC votes, a rural populist Conservative party will win a significant number of seats.
1) The party did not really run any sort of campaign
2) The party had very few members in 2009, now they have between 3000 and 5000
3) They have the active support of a number of former Conservative/CA/Reform MPs. They also have former Newfoundland Premier Brian Peckford stumping for them.
4) They have money in the bank for a campaign
At this point the Conservatives are in range to to have a chance to win in:
Peace River North and Peace River South, though south is a long shot.
Nechako Lakes
Cariboo North
Cariboo Chilcotin
All 7 ridings in the Okanagan
Fraser Nicola
Abbotsford South
That is 16 ridings
One more that could be in play is the one John Cummins runs in, which is likely to be Richmond East or Delta South
I base my estimates on where they can win on the 1991 Social Credit wins, 1996 BC Reform wins, and ridings the federal Reform/CA/Conservatives have consistently won with a majority in the last seven elections.
The Conservatives may cause about 10 Liberal ridings to change to NDP through a shift in support. 2 Kamloops ridings, 2 PG ridings, Comox, Parksville and four in the Lower Mainland
Éric 03 June, 2011 14:37
Once we get closer to an actual election, I will develop a more sophisticated model. I am using a sort of uniform swing model for the time being that has little other input.
Kyle H. 03 June, 2011 15:37
From what I know of BC, Bernard just has it about right; the old bases for the conservative SoCred factions will be the Conservative's greatest areas for growth, though whether or not they can break into the Lower Mainland is questionable. Unless they get a huge bump in the polls, they'll be restricted most likely to rural BC, in southwest corner, with dots here and there in the north and central BC, and possibly a seat or two in Langley, Abbotsford, and Surrey.
You can look at the 1996 results.
The Liberals had a higher popular vote yet the NDP eked out a majority as the Reform BC party split crucial ridings as per Bernard's comment.
is there a seat projection for the latest Harris-Decima?
Ira 03 June, 2011 16:27
I expect that new parties coming out of nowhere would be difficult to project. Imagine projecting the 1993 federal election. You might have had some idea where the Reform support was, because they ran in 1988, but the Bloc support likely would have been a complete mystery.
I look forward to your BC model (though I recognise that other provinces are more pressing concerns), but I don't envy your task.
I do wonder if BC will see an early election depending how the HST referendum goes. I also wonder how the HST referendum will go if there's a postal strike.
AverageCanuck 03 June, 2011 17:11
I don't see how very much of this could be confusion over the federal Conservative party.
If this poll was conducted in the same manner as the last poll in which the BC CP got 2% then one would suspect that the 'confused' were included in that total. Perhaps a confusion level of 1.5% considering they only got .5% in the previous election.
But then again they are now led by a former CPC MP. Sure Strahl, Hill, and Day are going with Clark.
But a lot of other old reform/alliance types like Randy White are going with Cummins.
18% seems realistic to me. People keep saying his pro-life, pro-marriage message will hurt him.
But in the bible belt around Chilliwack and areas in the interior and north that kind of talk is actually pretty popular.
You realy do hit a ceiling of around 20% though, concentrated in those areas because at the same time that kind of talk is toxic on the island and in Vancouver.
Still high concentrated support = seats.
Courtenay Bound 03 June, 2011 17:50
Sorry but as right wing as I am and I swing pretty far to the right I would not be considering the BC Conservatives to be legitimate players. Sure lots can happen between now and the eventual election call. Problem for the BC Conservatives is that we know who these people are. They were the unrepentant rump of the now dead Social Credit Party. When that party went bust they became BC Reform Party. They've been intermingled with the BC First Party.
What they don't realize is that the right in BC has changed a lot. It's more cosmopolitan, more sophisticated, and more educated today and far less of the Bible thumping variety. I mean come on but Cummins said being gay was a choice. That won't even fly in northern BC.
The best thing the BC Conservatives could do is close up shop before they really embarrass themselves anymore.
pinkobme 03 June, 2011 18:46
I would just add one observation to Bernard's solid analysis. Because BC's politics tends to split between two parties, left and right, the emergence of a reinvigorated Conservative party poses a life-and-death threat to the Liberals. Generally the right is represented by a party made up of an amalgamation of conservative-type parties. The Socreds were the right power brokers for about 40 years before they collapsed in the early 90s and the Liberals took over. But BC right-wingers apparently aren't afraid to jump ships at the blink of an eye. If Eric is right and Clark appears to be swinging the Liberals toward the center, the Conservatives could gain a great deal of support by the next election, which is not likely for almost two more years. That would leave the Liberals squished between the Conservatives on the right and the NDP on the left, in other words, the BC political wasteland. This may be pushing thigs a little, but we could even have defections from the Liberals to the Conservatives in the Legislature before the election. That could happen if it's apparent to right-leaning Liberal MLAs their party is doomed and they'd want to save their own skins.
Dix of the NDP must love this.
Pinkobme don't be too sure about vote splitting just yet.
Dix and the NDP are very left wing. Cummins is very right wing.
Usually parties try to hug the centre like in the last federal election which squeezed out the Liberals.
In this case Clark might just hold enough sway with moderate, middle of the road types to win a plurality of seats.
Prediction: Minority Liberal gov't.
Danger for the Conservatives is that this is about where the Greens usually poll, maybe a tad over but the left-wing piggy backer on the NDP who never quite pan out could be the Conservative's model as a right-wing piggy backer for the BC Liberals.
Hey AverageCanuck, you could well be right and I could be out to lunch. After all, I was the guy who predicted the Libs would gain 15 or 20 seats in the last federal election. Need I say more.
However, I would just argue that this time the BC Conservatives are lead by a former federal tory who's well versed in incrementalism. If Clark goes too far toward the center, he'll take the right from her and it'll make it difficult, if not impossibe, for her to win. The NDP would form the government and Cummins and his crew would pick away at what was once the party of the right (Liberals). One or two terms of that and it'll be Premier Cummins. It's a game the BC Liberals played against the Socreds and the federal Reform Party used on the PCs.
Again though, it's two years to the next election, so who knows?
I'm not surprised by this poll, my parents in BC just bought Conservative memberships.
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[To v3.0 forum] > v2.0 pre-2020 archive Board Index < Electric Universe - Planetary Science
Electric Jupiter
Historic planetary instability and catastrophe. Evidence for electrical scarring on planets and moons. Electrical events in today's solar system. Electric Earth.
Unread post by StefanR » Tue Mar 18, 2008 7:54 pm
Press Release - New discovery at Jupiter could help protect Earth-orbit satellites
Issue date: 09 Mar 2008
Number: 07/08
Radio waves accelerate electrons within Jupiter’s magnetic field in the same way as they do on Earth, according to new research published in Nature Physics this week. The discovery overturns a theory that has held sway for more than a generation and has important implications for protecting Earth-orbiting satellites.
Jupiter illustration - Production of synchotron radiation from JupiterUsing data collected at Jupiter by the Galileo spacecraft, Dr Richard Horne of British Antarctic Survey (BAS) and colleagues from the University of California, Los Angeles, and the University of Iowa found that a special type of very low frequency radio wave is strong enough to accelerate electrons up to very high energies inside Jupiter’s magnetic field.
According to lead author, Dr Richard Horne,
“We’ve shown before that very low frequency radio waves can accelerate electrons in the Earth’s magnetic field, but we have now shown that exactly the same theory works on Jupiter, where the magnetic field is 20,000 times stronger than the Earth’s and the composition of the atmosphere is very different. This is the ultimate test of our theory.”
“On Jupiter, the waves are powered by energy from volcanoes on the moon Io, combined with the planet’s rapid rotation – once every 10 hours. Volcanic gasses are ionized and flung out away from the planet by centrifugal force. This material is replaced by an inward flow of particles that excite the waves that in turn accelerate the electrons.”
Understanding how electrons are accelerated will help scientists make better predictions of when satellites are at risk of damage by high-energy charged particles.
These particles encircle the Earth in the Van Allen radiation belts and can damage satellites by causing malfunctions and degrading electronic components.
However, the number of particles in the radiation belts can change dramatically within a few minutes, which is why more accurate forecasting is needed.
The discovery also has other scientific implications for Jupiter – it overturns a theory that has held sway for more than 30 years. According to Dr Horne,
“For more than 30 years it was thought that the electrons are accelerated as a result of transport towards Jupiter, but now we show that gyro-resonant wave acceleration is a very important step that acts in concert. Once the electrons are accelerated, they are transported closer to the planet and emit intense synchrotron radiation out into interplanetary space. Our theory provides the missing step to explain this high intensity radiation from Jupiter, which was first detected on Earth more than 50 years ago.” ****their theory provides blablabla (I woke up and got paid)****
Issued by the British Antarctic Survey Press Office.
The paper ‘Gyro-resonant electron acceleration at Jupiter’, is published in Nature Physics on 9 March 2008.
Linda Capper - tel: +44 1223 221448, mob: 07714 233744, email: l.capper@bas.ac.uk
Author Contact: Dr Richard Horne - tel: +44 1223 221542, mob: 07786 733667, email: R.Horne@bas.ac.uk
Wave acceleration
The waves accelerate the electrons by a process known as gyro-resonance – a process where the electrons spiral around the Earth’s magnetic field at the same rate as the waves rotate around the magnetic field – around 3,000 times a second, or 3 kiloHertz. The waves were found to be particularly strong outside the orbit of Jupiter’s moon Io and are known as whistler mode chorus waves. The same waves are found in the Earth’s magnetic field and are measured by BAS scientists in the Antarctic.
Van Allen radiation belts
Jupiter, like the Earth, has belts of energetic charged particles (electrons and ions) that surround the planet like a ring doughnut. They are named after James Van Allen who discovered the Earth’s radiation belts 50 years ago using the first US satellite, Explorer I. Jupiter’s belts were also discovered by Van Allen when Pioneer 10 flew past the planet in 1973 on its way to the outer planets. Jupiter’s magnetic field constrains the particles to move in a spiral along the magnetic field. The particles ‘bounce’ between mirror points in the northern and southern hemispheres, and drift around the planet.
Galileo spacecraft
Launched by the space shuttle in October 1989, the NASA spacecraft Galileo was sent to explore Jupiter and its moons, reaching the planet in December 1995. Unfortunately the high-gain antenna failed to deploy properly and the spacecraft could only send a trickle of information back to Earth via its low-gain antenna. Nevertheless, several important new discoveries were made about Jupiter, its moons, magnetic field and particles. As a result, NASA is planning another mission, called Juno, which will study Jupiter’s atmosphere, auroral light emissions, and magnetic field. Juno is due for launch in 2011.
Space and Antarctica
Antarctica is our 'window on space'. Magnetic space storms damage spacecraft, disrupt power supplies, communications and navigation systems and alter satellite orbits. British Antarctic Survey (BAS) scientists are attempting to predict space weather through a better understanding of the complex process that take place when the Earth and Sun's magnetic fields meet. BAS scientists use several different technologies to measure variations in the Earth's magnetic field. Data from these studies are used in mathematical models to test theoretical ideas. This research makes a major contribution to international global research programmes that involve spacecraft and networks of ground-based scientific instruments.
British Antarctic Survey is a world leader in research into global issues in an Antarctic context. It is the UK’s national operator and is a component of the Natural Environment Research Council. It has an annual budget of around £40 million, runs eight research programmes and operates five research stations, two Royal Research Ships and five aircraft in and around Antarctica. More information about the work of the Survey can be found at: http://www.antarctica.ac.uk.
http://www.antarctica.ac.uk/press/press ... php?id=350
Last edited by nick c on Fri Mar 25, 2011 9:13 am, edited 1 time in total.
Reason: Title changed for thread merger
The illusion from which we are seeking to extricate ourselves is not that constituted by the realm of space and time, but that which comes from failing to know that realm from the standpoint of a higher vision. -L.H.
Re: New discovery at Jupiter
Unread post by MGmirkin » Wed Mar 19, 2008 12:09 am
*Laughs silently*
I love it... It seems they're just overturning all the money-changer's tables in the temple of science...
The discovery overturns a theory that has held sway for more than a generation and has important implications [...]
Yes, I'm certain it does! Perhaps they read my article "X-rays Betray Giant [Electrical] Particle Accelerator in the Sky."
The long and short of it. Particle accelerators tend to operate in much the same way whether man-made or naturally occurring. Consider what is said of accelerators over at Hyperphysics:
[quote="The "synchrotron" article"]Acceleration is achieved by the application of radio frequency electric fields at RF cavities along the circumference of the ring.
Such accelerators can be used with protons or electrons, and even with heavier positive ions.[/quote]
http://hyperphysics.phy-astr.gsu.edu/hb ... synch.html
[quote="The "linear accelerator" article"]As long ago as 1928, R. Wideroe demonstrated that electrons could be accelerated through a tube by applying a radio frequency voltage to separated sections of the tube so that the electrons felt an accelerating electric field when they passed the gap. If it was arranged so that the electrons arrived at the next gap at the right phase of the RF voltage, they would be accelerated again, getting double the energy they would have gotten from just the application of the maximum field of the RF.
The linear particle accelerator is an extension of Wideroe's idea to a long linear array of accelerating "cells" powered by a radio frequency source in the megawatt power range and in the gigahertz frequency range.[/quote]
http://hyperphysics.phy-astr.gsu.edu/hb ... linac.html
The long and short of it seems to be that particle accelerators work by using radio frequency electric fields... Quelle surprise! Now it seems to be that "Radio waves accelerate electrons within Jupiter’s magnetic field in the same way as they do on Earth..." Say it ain't so! Et encore, quelle surprise!
Not only that, but "[t]he discovery overturns a theory that has held sway for more than a generation and has important implications..."
Moreover, it also seems that theories that have held sway about the sun for some odd 30 years are in the process of being overturned, as well!
(Waving goodbye to a standard model [of the sun])
http://sprg.ssl.berkeley.edu/%7Etohban/ ... icle_id=68
More discussion on that bit over at the thread in the Electric Universe part of the forum.
Seems like space- / solar- / astro-physics is getting a good shake-up lately. Good! It needs it...
They finally seem to be getting a little plasma / electricity in their diet! Mmm, metallic tasting!
Unread post by MGmirkin » Tue Mar 25, 2008 5:18 pm
For some reason the prior link wasn't working, so I've grabbed the other versions of the article here:
http://www.spacedaily.com/reports/New_D ... s_999.html
http://www.physorg.com/news124293097.html
Hopefully, those links should be good for the foreseeable future...
Contact FS3
more from Jupiter
Unread post by FS3 » Wed Mar 26, 2008 4:30 pm
It´s not so uncommon these days that electric circuits are found. You only have to search a little bit:
From Basics of Radio Astronomy:
...Most of the radiation from the Jupiter system is much stronger at longer wavelengths than
would be expected for thermal radiation. In addition, much of it is circularly or elliptically
polarized—not at all typical of thermal radiation. Thus, it must be concluded that non-thermal
processes similar to those taking place in galaxies are at work. That is, ions and electrons accelerated
by the planet’s spinning magnetic field are generating synchrotron radiation...
...As a matter of fact, a predominant feature of Jupiter’s magnetosphere is the plasma torus that
surrounds the planet, corresponding closely with the orbit of Io, which is at about five Jupiter
radii. It is an intensely radiating plasma within a slightly less active outer plasma. To add to the
adventure, as Io orbits through the magnetic field lines, an electric current of up to 5 million
Amps is generated between Io and the planet! Where this current reaches the atmosphere of
Jupiter, it generates strong radio frequency emissions that can be associated with the orbital
position of Io. The current also generates auroras in the upper atmosphere of Jupiter...
junglelord
Unread post by junglelord » Mon Apr 14, 2008 9:36 am
Jupiter in a soap bubble...yeah a soap bubble
http://www.aip.org/pnu/2008/split/860-3.html
I do not doubt that we can scale a Red Spot, thats kinda cool
Its not jupiter in a soap bubble...
If you only knew the magnificence of the 3, 6 and 9, then you would have a key to the universe.
— Nikola Tesla
Casting Out the Nines from PHI into Indigs reveals the Cosmic Harmonic Code.
— Junglelord.
Knowledge is Structured in Consciouness. Structure and Function Cannot Be Seperated.
— Junglelord
Jupiter finally goes "electric"!
Unread post by FS3 » Fri May 02, 2008 6:16 am
Another nail in the coffin of the Astrocomical Standard Model has been reported from Jupiter. Its rings have been explained by electrical interaction with the field of the Sun. Although tempered down by "interactions of light and shadow" this new study by University of Maryland´s professor Douglas Hamilton and German co-author, Max Planck´s Harald Krüger - based on data from spacecraft Galileo traversal of Jupiter's rings in 2002-2003 - hold the potential of even more relevations:
From Jupiter's Rings Are Shaped By Interplay Of Sunlight And Shadow
"...As they orbit about the planet, dust grains in the rings alternately discharge and charge when they pass through the planet's shadow. These systematic variations in dust particle electric charges interact with the planet's powerful magnetic field. As a result small dust particles are pushed beyond the expected ring outer boundary, and very small grains even change their inclination, or orbital orientation, to the planet..."
Just consider that the Roche-Limit of Jupiter is given at appr. 71.500km. Outside of this gravitationally calculated constant it is stated"that NO RINGS should be possible". This promises to be interesting, as the rings of Jupiter do have a diameter beyond 640.000km…
As I suggest the "solution" will be a necessary mass "recalculation" of Jupiter...
Never forget that ALL DATA on masses of our celestical bodies are MATHEMATICALLY DERIVED FROM their paths and Newton´s Laws. So it may be easy to change them again and again - up to the needs - and not according to reality. But it may be the same as taking away stones from an old building. If you take away too many of them - the whole construct may tumble and fall down, finally.
And in the end even our Sun may turn out to be much more "lighter" than previousely thought - finally crushing all what was speculated about "thermodynamical fusion", nuclear fission from the core etc. etc...
They may have to run after their "missing masses" soon.
(FMV 5-25-08: Edited title to be more general per new directions the thread has taken aside from just the rings of Jupiter.)
Re: Jupiters finally goes "electric"! The CHARGED rings
Unread post by MGmirkin » Fri May 02, 2008 10:07 am
I've wondered elsewhere whether this is analogous to the Earth-moon interaction(s) around full moon. IE, the tickle from Earth's plasma tail, which points in the antisunward (away from the sun) direction. One might call that the "shadow" side of Earth. I'm wondering if Jupiter's "shadow" side is also its "plasma tail" ("magnetotail"; assuming it has one) side. If so, are the dust grains charging and discharging as they pass through its plasma tail? Currents, double layers, and all that...?
Perhaps it comes back to Birkeland, once more:
(The Norwegian Aurora Polaris Expedition 1902-1903 -
Chapter VI. On Possible Electric Phenomena in Solar Systems and Nebulae)
http://www.plasma-universe.com/index.ph ... nd_Nebulae
Specifically, figure 257...
Unread post by FS3 » Fri May 02, 2008 3:31 pm
Another thread of this forum, New discovery at Jupiter, may include some more details from the recent findings. Especially, regarding that "plasma tail".
Thank you, MGmirkin, again for adding further facts that I forget to mention - as I thought that regulars of this forum should know about the fact that it was Kristian Birkeland, who was laying out the basics to this "new" findings with his famous Terrella-experiments more than 100 years ago.
More than 100 years ago...
Unread post by Eres » Fri May 02, 2008 11:32 pm
FS3 wrote: Just consider that the Roche-Limit of Jupiter is given at appr. 71.500km. Outside of this gravitationally calculated constant it is stated"that NO RINGS should be possible". This promises to be interesting, as the rings of Jupiter do have a diameter beyond 640.000km…
Never forget that ALL DATA on masses of our celestical bodies are MATHEMATICALLY DERIVED FROM their paths and Newton´s Laws.
Very interesting. This idea can also be worth for some orbitting Saturn's satellites inside the Roche's limit and therefore for the mass of Saturn in relationship to its electric condition and the electric environment.
Dmitriev's Thoughts on Jupiter / Io Plasma
Unread post by Sandra Rodriguez » Sun May 11, 2008 10:23 pm
In Shedding Some Light On Jupiter we read:
“More than four years ago Picture of the Day articles addressed the "volcanic" plumes on Jupiter's moon Io and demonstrated that they are plasma discharges from the moon to the gas giant. Some planetary scientists later began to acknowledge the electrical connection between them when Io's "footprint" was seen in the polar aurora on Jupiter. “
I am not a scientist, only an avid reader of Thunderbolts. Therefore, I feel uneasy about asking questions on matters that are certainly way above my full understanding. Still, I must say that the subject of the electrical connection between Jupiter and Io was addressed by Dr. Alexey Dmitriev in Planetophysical State Of Earth And Life, published January 8, 1998 by the Millenium Group:
http://www.tmgnow.com/repository/global ... sical.html
My question would then be: is it possible that scientists “in the West” were not paying attention to Dmitriev’s findings? Following is the pertinent quote from Dmitriev’s essay, which I would like you to share your thoughts on:
“The doubling of the magnetic field intensity on Jupiter (based upon 1992 data), and a series of new states and processes observed on this planet as an aftermath of a series of explosions in July 1994 [caused by "Comet" SL-9] [12].
That is, a relaxation of a plasmoid train [13,14] which excited the Jovian magnetosphere, thus inducing excessive plasma generation [12] and its release in the same manner as Solar coronal holes [15] inducing an appearance of radiation belt brightening in decimeter band (13.2 and 36 cm), and the appearance of large auroral anomalies and a change of the Jupiter - Io system of currents [12, 14].
Update Note From A.N.D Nov. 1997:
A stream of ionized hydrogen, oxygen, nitrogen, etc. is being directed to Jupiter from the volcanic areas of Io through a one million amperes flux tube. It is affecting the character of Jupiter's magnetic process and intensifying its plasma genesis.{Z.I.Vselennaya "Earth and Universe" N3, 1997 plo-9 by NASA data}
Moreover, the Ulysses spacecraft, traversing high heliospheric latitudes, recorded the absence of the magnetic dipole, which drastically changed the general model of heliomagnetism, and further complicated the magnetologist's analytic presentations.
The most important heliospheric role of coronal holes has now become clear; to regulate the magnetic saturation of interplanetary space. [28,30].
Additionally, they generate all large geomagnetic storms, and ejection's with a southerly directed magnetic field are geo-effective [22].
There is also existing substantiation favoring the solar winds effects upon Earth's atmospheric zone circulation, and lithospheric dynamics [31].
The 23rd cycle was initiated by a short series of sunspots in August 1995 [32], which allows us to predict the solar activity maximum in 1999. What is also remarkable, is that a series of class C flares has already happened in July 1996.
The specificity and energy of this cycle was discussed at the end of the 1980's. [23]. The increased frequency of X-Ray flux flares which occurred in the very beginning of this cycle provided evidence of the large-scale events to come; especially in relation to an increase in the frequency of super-flashes.
The situation has become extremely serious due to the growth in the transmitting qualities of the interplanetary environment [2 3, 24] and the growth of Jupiter's systems heliospheric function; with Jupiter having the possibility of being shrouded by a plasmosphere extending over Io's orbit [13].
As a whole, all of the reporting and observation facilities give evidence to a growth in the velocity, quality, quantity, and energetic power of our Solar System's Heliospheric processes.”
Thank you in advance for your comments.
sarodgz@gmail.com
(FMV 5-16-08: Modified thread title to accurately and specifically reflect topic of conversation.)
Re: JUPITER AND IO
Unread post by StefanR » Mon May 12, 2008 7:47 am
Sandra Rodriguez wrote: I am not a scientist, only an avid reader of Thunderbolts. Therefore, I feel uneasy about asking questions on matters that are certainly way above my full understanding. Still, I must say that the subject of the electrical connection between Jupiter and Io was addressed by Dr. Alexey Dmitriev in Planetophysical State Of Earth And Life, published January 8, 1998 by the Millenium Group:
My question would then be: is it possible that scientists “in the West” were not paying attention to Dmitriev’s findings?
Goodday Sandra,
That is a interesting link you gave there. I'm no scientist either, so I feel uneasy answering questions above my understanding
But to try to give you my take on your question, I would say that sometimes the cultural/language barrier sometimes plays a role in the 'East'/'West' relations. But I think slowly more and more those divides are disintegrating on the Internet, which is a good thing of course.
On reading the article there are surely some very interesting relations pointed out which are subject of this Forum too. And as the 'East' has had it's own space and science programs which did not always communicate fully with what happened in the 'West'. So I think it is possible that some results or hypotheses have been 'there' for a little longer than 'here'. Where ever here and there are, of course.
Also the mindset of the mainstream in the 'west' was not tolerant for ideas like Dmitriev's. But things are changing slowly I think and the Internet is a very valuable tool for that, I think.
The only difficulty I have with some of the more "doomsday" conclusions can maybe be a little presumptious. The increased level of quantative and qualitative detections and observations, can maybe be misleading in detecting cycles and episodes.
What are your thoughts about that?
PS. maybe for some tornado-interested forum-members there may be some interesting articles too, like:
http://www.tmgnow.com/repository/planetary/tornado.html
Unread post by nick c » Mon May 12, 2008 9:08 am
Sandra, welcome to the forum:
Thanks for that link. That is a very interesting article. Dr. Alexey Dmitriev wrote the article in 1998, I wonder what he has written since then?
Sandra Rodriguez asked:
is it possible that scientists “in the West” were not paying attention to Dmitriev’s findings?
Yes, it could be that it is being ignored because it goes against the human-caused global warming axis which is currently so politically powerful.
color emphasis mine
The Earth's temperature regime is becoming more, and more, dependent on external influences.
As StefanR pointed out, it is also possible that the article is not commonly distributed, due to the barriers resulting from the East/West gap, and many scientists are simply not aware of it. Those that are, probably would not pass it on to their colleagues because it is perceived as "fringe." Dr. Dmitriev subscribes to the 'Plasma Universe' school of thought, which makes mainstream (gravity is all you need) science uneasy.
I would also question, the doomsday aspect. We seem to encounter this 'chicken little syndrome' in many areas. Though, perhaps we should worry if we are moving into a galactic region that is putting increasing electrical stress on the Sun and the solar system.
I wonder if there is an implication (from the article) that we could be seeing some increased visual effects such as enhanced auroras, or perhaps one or more of a solar system objects' plasmasphere going from dark to glow mode? due to increased electrical stress. Any connection to the Comet Holmes' flare up? Or is one of the gas giants about to become a brown dwarf? Is that possible?
GaryN
Location: Sooke, BC, Canada
Unread post by GaryN » Mon May 12, 2008 2:01 pm
I believe Dr.Alexey Dmitriev is correct. If we are to pass through the central plane of the galaxy then we will be passing through areas of higher density plasma. If we pass through one of the star forming arms, then the plasma density would be even higher, and the electrical activity much more energetic. This image would indicate we may pass through the plane in a less plasma dense gap between the spiral arms:
http://www.news.wisc.edu/newsphotos/ima ... _sun05.jpg
I'm still planning on building a Faraday cage for 2012!
In order to change an existing paradigm you do not struggle to try and change the problematic model. You create a new model and make the old one obsolete. -Buckminster Fuller
Unread post by MGmirkin » Mon May 12, 2008 3:12 pm
GaryN wrote: I'm still planning on building a Faraday cage for 2012!
So, how many seats you gonna' have in there? Bucket or otherwise... Taking reservations in advance?
Is it compatible with FoilHat(TM) technology?
*Tongue planted firmly in cheek...*
All in good fun!
Return to “Electric Universe - Planetary Science”
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Home › Breaking News › The 'Cover-Up', how high does it really go on Fast and Furious?
The 'Cover-Up', how high does it really go on Fast and Furious?
Posted on December 2, 2011 by bcse
By Scott W. Winchell, Editor – Just when we thought the Fast and Furious debacle was so reprehensible that numerous Congressmen, from both parties, joined a growing cacophony of calls from the blogo-sphere and media pundits for the resignation of US Attorney General Eric Holder it takes an even bigger twist.
SUA and many others have pointed out that the political ideology of current administration officials set the stage for such a debacle but its not just about Holder’s lies anymore, it goes further, into a blatant cover-up that may reach all the way up to the White House.
FBI Director Mueller, AZ Gov. Brewer and AG Holder
It now appears that the death of Border Patrol Officer Brian Terry was clearly avoidable, if only the FBI and DEA had practiced proper ‘deconfliction’, or more precisely, talked to each other, local authorities, and Border Patrol to avoid conflicts between cases, especially involving informants. Not informing Border Patrol of ongoing, extremely dangerous operations in an infamous area called “Smuggler’s Paradise” in Pima County Arizona’s Peck Canyon was unconscionable.
One must also wonder if Pima County Sheriff Clarence Dupnik now famous for his outspokenness after the Gabby Giffords incident, knew anything was happening either. After all, it was happening in his jurisdiction and it was in an area Border Patrol frequently performed patrols as part of its duties.
Eric Holder and Janet Napolitano
The timing is also very curious here because Giffords and 19 others were shot on January 8, 2011, just a few weeks after Brian Terry was killed on December 14, 2010 and President Obama immediately sent FBI Director Mueller to the area to personally handle the situation. Why? The unprecedented move was curious at the time, but since a Congresswoman was a victim, it seemed to be a deft move, if not a political move, or was it?
Questions now arise that since both incidents happened within Pima County, within mere weeks of each other, the White House may have been worried the two may be related. Or possibly that with all that new publicity, the DoJ and the White House did not want prying eyes seeing anything related to the Terry death.
Additionally, questions rise that DoJ operations intentionally withheld information from DHS to cover for their own ineptitude prior to the incident where Terry was killed. Not informing Border Patrol of a building incident directly caused Brian Terry and his team to walk into a heavily armed ‘rip crew’ operation.
Terry had no way to defend himself facing much heavier ordnance, assault rifles that came from Fast and Furious operatives. In fact, one weapon is now missing, and the case has been sealed.
Janet Napolitano told Congress she never talked to DoJ about the killing of Brian Terry, but we now know that a debacle like this had to filter up to the top, especially since it happened so close to the Giffords incident. Her staff had to know what took place between agencies and with all the new publicity, it must have been discussed by everyone in DHS. It is simply unbelievable that she would not have confronted DoJ about such insanity unless she was directed to keep silent by the White House.
If Holder does resign, along with others, are they going to be liable for abetting a crime after the fact? What if Issa and others prove culpability and confront Holder when he testifies again on December 7th and demand his resignation right there in the hearing room? We can only hope.
FBI Criminal Informant Complicit in Brian Terry’s Death (PJM Exclusive)
From multiple sources come shocking charges of deadly ineptitude and an FBI coverup in Fast and Furious.
By Bob Owens
In the growing Fast and Furious scandal, Border Patrol Agent Brian Terry’s death in Peck Canyon, Arizona was previously described as a chance meeting that led to a firefight: an illegal alien “rip crew” working for the Sinaloa cartel was hoping to find other illegal aliens and to rob them at gunpoint. Instead, they stumbled across a Border Patrol unit and murdered Agent Terry.
Last week, the Washington Times offered a new version of the encounter: they reported that the rip crew was not hunting illegals, but Border Patrol teams — with the intention of engaging them in combat.
Sources now tell PJ Media that neither version of events is accurate: the rip crew was not waiting for a chance encounter with other illegals, nor did the members intend to engage American law enforcement agents.
The rip crew was in Peck Canyon that evening with the intention of stealing money and drugs from a specific shipment of which they had prior knowledge.
Sources claim the Department of Justice has been trying for almost a year to hide the key information — how the rip crew knew the shipment was coming through that night.
Criminal informants (CIs) are a common tool of law enforcement agencies. When agencies apprehend criminals, agencies often reduce or drop charges in exchange for information leading to the arrests of higher-ranking criminals. Earlier this year, reports claimed that Operation Fast and Furious weapons smuggled over the border were actually chosen by an FBI informant, and paid for with money provided by the federal government.
The rip crew knew to be in Peck Canyon that December evening because a CI working for the FBI found out about a smuggling run — from the FBI.
It is not clear if the information was provided intentionally, but a possible motivation for the FBI to provide the information is known to exist: the CI had previously lost a shipment of drugs, and wanted to regain the trust of the cartel with an offering of drugs or money. The other possibility is that the FBI mistakenly allowed the CI to discover the information.
The CI used this information to organize an ambush of the drug convoy. A source tells PJM that the FBI knew from wiretaps that the CI was using their information to set up an ambush.
The Drug Enforcement Administration (DEA) — through its own CIs and communications intercepts — was also aware of the planned assault.
Neither the DEA nor FBI warned Border Patrol about the expected criminal activity.
The federal government will still not reveal if one of the two WASR-10 AK-pattern semi-automatic rifles located near the scene — provided to the Sinaloa cartel via Operation Fast and Furious — was the weapon that put a bullet through Brian Terry’s heart. The existence of a third recovered gun, an SKS carbine, has been disputed by the FBI despite the fact it had been talked about openly in the beginning of the investigation among federal agents.
Multiple sources tell PJM that this third weapon “disappeared” because it was the weapon carried by the FBI CI who ran the rip crew. When it was recovered near the scene of the murder and subsequently traced by the ATF, it traced back to the FBI CI via the gun shop in Texas where it was purchased.
Deconfliction is a major element of high-risk undercover law enforcement work. Undercover agents and informants often cross jurisdictional paths, and deconfliction is the process whereby agencies warn off other agencies so that their assets don’t end up in conflict, putting investigations and lives at risk.
In this case, the FBI and DEA failed to deconflict. Neither agency bothered to warn Border Patrol to keep their BORTAC teams out of Peck Canyon that evening. As a direct result of this FBI and DEA failure — combined with Homeland Security forcing BORTAC units to carry less-lethal beanbag rounds in some of their primary weapons — Brian Terry’s under-armed four-man unit walked into an ambush against a heavily armed rip crew, at least five of whom were carrying rifles.
Brian Terry’s murder was entirely preventable. The incompetence of the DEA and FBI let his Border Patrol unit walk into an ambush. After the ambush, it appears the FBI tampered with evidence to cover up that one of their informants was involved with the murder of a federal agent.
The government has recently sealed the case against the only suspect the FBI chose to keep behind bars.
Posted in Breaking News, Politics-DC
Tagged with Brian Terry, DEA, Fast & Furious, FBI, Gabby Giffords, Gunwalking, holder, Mueller, Napolitano, Pima County
← Commander-'Do-Nothing'-in-Chief – Party of 'Do-Nothings'
Demonstrators linked to bomb threat? – Lessons will be learned →
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Election to membership within the NAS is considered one of the highest honors that a scientist can obtain. If both scientific research and political debates over such questions appear to drag on endlessly, surely one purpose is that now we have the improper expectations of science. Someone who thinks that science is all about certainty would possibly take a look at these altering understandings and resolve that nobody really knows what is going on – and tune the whole concern out. Yang paling banyak mendatangkan pertentangan adalah praktek poligami yang secara jujur dibenarkan oleh Joseph Smith ketika dia mengembangkan konsep hubungan keluarga yang baru. With science, you get suspense, drama, plot twists, surprises, fortifications,… Science is fun.
The systematic research of nature — what we today name science — was a definite domain, making little or no contribution to technological development. Science and the arts are both important to a well-rounded schooling, and that’s why we incorporate comic books and inventive activities into the STEM ideas of every month-to-month package. Apologia Science was designed by a former college professor to make the most of the very best methods to express concepts to kids so that they will be enthusiastic about …
The Internet has an enormous affect on how individuals talk, shop, and work. Furthermore, technology causes lots of distractions for students, affecting their studying. The answer, for Heidegger, is to not dispose of the technological way of regarding reality. It asserts that the technology moves along its personal path and that people have little affect over how these political systems, culture and social structure shall be impacted.
This whole Social motion was joined by eminent and well-known sports folks, Medical doctors, universities, and totally different institutions all through the United States, which has begun to boost the ire of many of those that had a rabid hatred of Obama and African people in America.
The shortcoming to entry the Internet is a consider encouraging extra individuals to start finding out once more.” (Gorard, Selwyn, & Madden, 2003 p.thirteen) Technology primarily based instruction is motivating learners to achieve literacy and marketable skills.
The Benjamin Franklin Scholars (BFS) program is a twin-degree program in the College of Engineering (COE) and the Faculty of Humanities and Social Sciences (CHASS) at North Carolina State College. These are all effects of phone technology which we can all readily think of. And there are a lot …
The Amish communities generally are against certain sorts of technology. To offer on-line social networking service which will be centered and reflecting of social community or social relations amongst people who share pursuits and actions Most social community companies are net based and provide means for users to interact over the internet.
A definition of digital actuality has always been difficult to formulate — the concept of an alternative existence has been pawed at for centuries — however the closest modern ancestor came to life in the fifties, when a handful of visionaries saw the likelihood for watching things on a screen that by no means ends, but the technology wasn’t but good enough to justify the idea.
Most occasions this suggestions can result in far more gratifying iterations of the technology sooner or later. In a latest collaboration between Fermilab scientists and hundreds of meters of laser may have found the very pixels of reality, grains of spacetime one tenth of a femtometer across.
Furthermore, new developments in cognitive science, nano-technology, and digital reality may at some point enable us to transcend what it means to be human as we speak. I assume thus listening to and studying what …
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Accueil << 1 >>
Blasco, F. R., McKenzie, D. J., Taylor, E. W., & Rantin, F. T. (2017). The role of the autonomic nervous system in control of cardiac and air-breathing responses to sustained aerobic exercise in the African sharptooth catfish Clarias gariepinus. Comp. Biochem. Physiol. A-Mol. Integr. Physiol., 203, 273–280.
Résumé: Clarias gariepinus is a facultative air-breathing catfish that exhibits changes in heart rate (f(H)) associated with air breaths (AB). A transient bradycardia prior to the AB is followed by sustained tachycardia during breath-hold. This study evaluated air-breathing and cardiac responses to sustained aerobic exercise in juveniles (total length similar to 20 cm), and how exercise influenced variations in f(H) associated with AB. In particular, it investigated the role of adrenergic and cholinergic control in cardiac responses, and effects of pharmacological abolition of this control on air-breathing responses. Sustained exercise at 15, 30 and 45 cm s(-1) in a swim tunnel caused significant increases in f(AB) and f(H), from approximately 5 breaths h(-1) and 60 heartbeats min(-1) at the lowest speed, to over 60 breaths h(-1) and 100 beats min(-1) at the highest, respectively. There was a progressive decline in the degree of variation in f(H), around each AB, as f(AB) increased with exercise intensity. Total autonomic blockade abolished all variation in fH during exercise, and around each AB, but f(AB) responses were the same as in untreated animals. Cardiac responses were exclusively due to modulation of inhibitory cholinergic tone, which varied from >100% at the lowest speed to <10% at the highest. Cholinergic blockade had no effect on f(AB) compared to untreated fish. Excitatory beta-adrenergic tone was approximately 20% and did not vary with swimming speed, but its blockade increased f(AB) at all speeds, compared to untreated animals. This reveals complex effects of autonomic control on air-breathing during exercise in C. gariepinus, which deserve further investigation. (C) 2016 Elsevier Inc. All rights reserved.
Mots-Clés: Adrenergic tone; bass dicentrarchus-labrax; cardiorespiratory interactions; Cholinergic tone; Fishes; Heart rate; heart-rate; hoplerythrinus-unitaeniatus; Hypoxia; oxygen-tensions; rainbow-trout; salmo-gairdneri; Swimming; synbranchus-marmoratus
http://www.umr-marbec.fr/r3fbas3/show.php?record=1714
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adaptive_camouflage
2018/11/01 01:16 unusualresearch Added superscript formatting.2018/11/01 00:38 unusualresearch Added link to Plasma Window Technology.2018/11/01 00:24 unusualresearch Adaptive Camouflage example usage2018/11/01 00:22 unusualresearch created
adaptive_camouflage [2018/11/01 00:24]
unusualresearch Adaptive Camouflage example usage
unusualresearch Added superscript formatting.
* NASA's Jet Propulsion Laboratory, Pasadena, California * NASA's Jet Propulsion Laboratory, Pasadena, California
{{ :pe:nasa_200.jpg?400 |}} {{ :pe:nasa_200.jpg?400 |}}
+ See also: [[star_trek_force_fields|Plasma Window Technology]]
+ for Propagating Particle Beams and Radiation from Vacuum to Atmosphere.
Lightweight optoelectronic systems built around advanced image sensors and display panels have been proposed for making selected objects appear nearly transparent and thus effectively invisible. These systems are denoted "adaptive camouflage" because unlike traditional camouflage, they would generate displays that would change in response to changing scenes and lighting conditions. Lightweight optoelectronic systems built around advanced image sensors and display panels have been proposed for making selected objects appear nearly transparent and thus effectively invisible. These systems are denoted "adaptive camouflage" because unlike traditional camouflage, they would generate displays that would change in response to changing scenes and lighting conditions.
The positions and orientations of all the image sensors would be slaved to the position and orientation of one image sensor that would be designated a master imager. The orientations would be determined by a levelling instrument sensed by the master imager. A central controller connected to an external light meter would automatically adjust the brightness levels of all the display panels to make them conform to the to ambient lighting conditions. The underside of the cloaked object would be illuminated artificially so that the display from the top of the cloaked object would show the ground as though in ambient light; if this were not done, then an obvious shadow-induced discontinuity would be seen by an observer looking down from above. The positions and orientations of all the image sensors would be slaved to the position and orientation of one image sensor that would be designated a master imager. The orientations would be determined by a levelling instrument sensed by the master imager. A central controller connected to an external light meter would automatically adjust the brightness levels of all the display panels to make them conform to the to ambient lighting conditions. The underside of the cloaked object would be illuminated artificially so that the display from the top of the cloaked object would show the ground as though in ambient light; if this were not done, then an obvious shadow-induced discontinuity would be seen by an observer looking down from above.
- The display panels could be sized and configured so that a common inventory of such panels could be used to cloak a variety of objects, without need to modify the objects. Sizes and weights of representative adaptive camouflage systems and subsystems have been estimated: The volume of a typical image sensor would be less than about 1 in.^3 ( 16 cm^3). A system to completely cloak an object 10 m long by 3 m high by 5 m wide would weigh less than about 100 lb (45 kg). If the object to be cloaked were a vehicle, then the adaptive camouflage system could readily be operated on power provided by the vehicle electrical system, without adversely affecting the operation of the vehicle. + The display panels could be sized and configured so that a common inventory of such panels could be used to cloak a variety of objects, without need to modify the objects. Sizes and weights of representative adaptive camouflage systems and subsystems have been estimated: The volume of a typical image sensor would be less than about 1 in.<sup>3</sup> ( 16 cm<sup>3</sup>). A system to completely cloak an object 10 m long by 3 m high by 5 m wide would weigh less than about 100 lb (45 kg). If the object to be cloaked were a vehicle, then the adaptive camouflage system could readily be operated on power provided by the vehicle electrical system, without adversely affecting the operation of the vehicle.
The Scene From Behind an Object would be displayed on panels on the front of the object. The effect of cloaking is illustrated in this simulated image of an armored vehicle with adaptive camouflage on one side only. The Scene From Behind an Object would be displayed on panels on the front of the object. The effect of cloaking is illustrated in this simulated image of an armored vehicle with adaptive camouflage on one side only.
adaptive_camouflage.txt
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Value Creation and Capture Framework released by Victorian Government
VICTORIAN Major Projects Minister Jacinta Allan last week released the State Government's Value Creation and Capture Framework, which aims to create maximum value for Victorians from the state's multibillion-dollar pipeline of major projects.
The Framework provides guidance to all government departments, business, industry and community sector partners on ways that government will generate more industry and skills development, affordable housing, open spaces, community facilities and energy efficiency from future projects.
The Framework will apply to all major projects and precinct developments in Victoria, with agencies required to explore all value capture and creation options in the development of their proposals.
In a statement, Ms Allan said the Australian Government has suggested that one type of value capture – beneficiary charging – could be used to replace, or be a condition of, grant funding from the Commonwealth Government.
"This has often been used as an excuse by the Commonwealth for providing Victoria less than eight per cent of national infrastructure funding," Ms Allan said.
"The Labor Government supports value capture, but also recognises the role of government to invest in better communities without charging those communities for it. The Government rejects this excuse by the Turnbull Government to deny Victoria the funding it deserves.
"The Labor Government is already using its massive pipeline of major infrastructure projects to put Victorians first, creating thousands of jobs."
Ms Allan said the new Framework will complement other State Government initiatives like the Major Project Skills Guarantee, which ensures that at least 10 per cent of all work on major projects in Victoria is done by trainees, apprentices and cadets.
"In addition, under our Local Jobs First Policy, strategic projects valued at over $50 million require companies to meet minimum local content requirements using local firms, materials, expertise and skills," she said.
More information is available from the Department of Premier and Cabinet website at <http://dpc.vic.gov.au/index.php/news-publications/value-creation-and-capture-framework>.
Victorian Government announces funding to fast-track completion of planning and design of North East Link - 23 April 2018
Land titles and registry functions of Land Use Victoria to be privatised - 12 March 2018
NSW and Victoria to gain more than $6bn for infrastructure projects after Snowy Hydro deal - 5 March 2018
Preferred route selected for Melbourne's proposed North East Link project - 28 November 2017
Five-year Victorian Infrastructure Plan released by State Government - 23 October 2017
Corridor options released for Melbourne's proposed North East Link - 14 August 2017
Latest Victorian Articles
Victorian Government defines affordable housing in amendment to planning legislation
Victorian Government announces new measures to protect the state's flora and fauna
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Thur, August 29
at Eastern Kentucky
Sat, Sept 14
Central Connecticut State
at Truman State
Sat, Oct 5
Sat, Oct 12
at San Diego
Sat, Nov 2
at Davidson
Sat, Nov 16
at Butler
Football on Facebook
Football on Twitter
Football on Instagram
Morehead State 14 0 0 13 27
Valparaiso 0 0 14 7 21
Morehead State at Valparaiso | November 09, 2019
MOR TD 04:45 HURST 27 Yd Pass From PAPPAS (FOSTER kick)
MOR TD 00:45 HUFFMAN 83 Yd Pass From PAPPAS (FOSTER kick)
VALPO TD 10:43 BITTNER 6 Yd Pass From DUNCAN (LATSONAS kick)
VALPO TD 06:54 REESE 4 Yd Pass From DUNCAN (LATSONAS kick)
MOR TD 10:51 HOLDER 74 Yd Pass From PAPPAS (FOSTER missed kick)
MOR TD 01:40 AGUERO 37 Yd Run (FOSTER kick)
VALPO TD 00:20 LAROSE 2 Yd Pass From DUNCAN (LATSONAS kick)
Stats at a Glance
3rd Down Conversions 7-15 9-18
4th Down Conversions 1-3 0-0
Passing (Comp-Att) 307 (17-30) 304 (30-48)
Rushing (Att) 107 (38) 22 (23)
Penalties 7-60 8-74
Possession 28:52 31:08
BoxscoreTeam StatsPlay-by-PlayDrivesDefense
Morehead State 27
Brown Field , Valparaiso, Ind.
Morehead State Edges Valpo at Brown Field
For the second consecutive week, the Valparaiso University football team came up six points shy on Saturday afternoon at Brown Field. Visiting Morehead State sprinted ahead 14-0 before a strong third quarter helped Valpo draw even, but the Eagles left Porter County with a 27-21 triumph.
Morehead State (5-5, 3-3 PFL) started the day with a gutsy call by implementing a fake punt in their own territory on the first possession of the game. A completed pass by the punter went for four yards on fourth-and-5, so Valpo took over on downs.
The Brown & Gold couldn’t cash in on the favorable field position after taking over at the Morehead 41, as the Eagles forced a three-and-out.
The Eagles struck first with 4:45 to go in the first quarter as Mark Pappas tossed a 27-yard score to Landon Hurst to cap a 12-play, 87-yard drive.
Morehead State’s next possession resulted in a quick strike as Pappas found Jordan Huffman for an 83-yard TD pass. That doubled the lead to 14-0 with 45 seconds to go in the opening quarter.
Neither team cracked the scoreboard in the second quarter, and the 14-0 Morehead State lead stood into the locker room.
Valpo’s offense had its best drive of the day to open the second half, going 60 yards on eight plays culminating with a six-yard TD pass from quarterback Chris Duncan (Woodland Hills, Calif. / Woodland Hills-Taft) to tight end Brett Bittner (Chicago, Ill. / St. Laurence) with 10:43 left in the third. The drive also featured a 25-yard pass to Oscar Lopez (Chelsea, Mass. / Revere [Vermillion CC]) and was set up by Lopez’s 32-yard kickoff return.
The Valpo momentum continued on Morehead State’s first offensive snap of the second half, as Nick Turner (Gurnee, Ill. / Warren Township) forced a fumble after a completed pass and Jamari Booker (Kentwood, Mich. / East Kentwood) recovered to give the hosts possession right back with a chance to tie the game.
The positives kept coming for Valpo as a seven-play, 54-yard drive ended with Ollie Reese (Franklin, Tenn. / Battle Ground) reaching out to make an impressive catch in the back corner of the end zone for a TD from Duncan. The extra point tied the game at 14 with 6:54 left in the third.
Valpo briefly appeared to take the lead on a pick six by Turner, but it was negated on a pass interference penalty. The defense finished the stop, however, and Valpo took over after a Morehead State punt.
Valpo attempted a 47-yard field goal on the final play of the third quarter. The lengthy attempt curled wide right.
The Valpo defense continued its stellar second half when the Morehead State quarterback fumbled and Cam Germain (West Palm Beach, Fla. / Dwyer) recovered at the Morehead State 13-yard line, setting up a golden chance to take the lead for the first time in the game.
The Eagles’ defense came through again, first forcing three straight stops, then a 23-yard field goal hit the right upright.
On the ensuing possession, a sack by Trejuan Purty (Maryville, Tenn. / Maryville [East Tennessee State]) set up third-and-long for Morehead State deep in their own territory. But on third-and-19 from the Morehead State 26, Ian Holder hauled in a pass from Pappas that he broke for 74 yards to put the Eagles back ahead. The extra point was blocked, so the Morehead State lead was 20-14 with 10:51 left in the game.
Valpo had first-and-goal from the five, but couldn’t punch it in. The drive resulted in a missed field goal from 36 yards out with 8:12 to play.
The Eagles went for it on a key fourth-and-2 from the Valpo 37 and Issiah Aguero carried one 37 yards for a score to boost the lead to 27-14 with 1:40 left in the fourth.
Valpo had one final gasp, pulling within six on a two-yard TD toss to Deuce Larose (Fort Lauderdale, Fla. / Cardinal Gibbons) with 20 seconds remaining. The ensuing on-side kick was recovered by the Eagles to secure the victory.
Inside the Game
After entering the week with seven receptions for the season, Lopez had six grabs in the first half.
Bittner’s TD catch was the first of his career. Duncan’s first TD pass of the day was the 20th of his career.
Reese hauled in his second touchdown catch both this season and in his career.
Germain’s fumble recovery was the first of his career.
Jaxon Peifer (Normal, Ill. / Normal Community) topped the team with 10 tackles.
The Larose TD grab was his third of the season and the fifth of his career.
Duncan passed for 304 yards and three scores, while Lopez was the top target with nine catches for 78 yards. Larose’s 112 receiving yards led the team.
It’s Hoosier Helmet Week as Valpo (1-9, 1-5 PFL) will visit rival Butler on Saturday for an 11 a.m. CT kickoff at the Sellick Bowl. The game will be broadcast on YouTube Live courtesy of Butler Athletics with the hometown call available on 95.1 FM Valparaiso. Links to live video, audio and stats will be available on ValpoAthletics.com.
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Tourist Tracks
Glasgow MP3 Audio Walking Tours
Download Glasgow Tour £5
Download Scotland Tour Pack (Edinburgh, Glasgow) £8
Download Glasgow Track 1 for free
We have a two-hour audio walk around Glasgow, which is available for £5, or can be bought together with our Edinburgh tour for £8. All our walks include a map in PDF format, which you will find within the zip file that you download immediately after purchase. Audio files are standard MP3 format, suitable for use on iPods and other MP3-compatible devices.
The route passes by some of the major cultural, historical and architectural highlights of central Glasgow, including: George Square; City Chambers; Gallery of Modern Art; Merchant City; Glasgow Savings Bank; Italian quarter; Ramshorn Kirk/Theatre; Tollbooth Steeple; Provand’s Lordship; St Mungo Museum of Religious Life and Art; Glasgow Cathedral; Necropolis; University of Strathclyde; Glasgow Royal Concert Hall; Willow Tearooms; Glasgow School of Art; Blythswood Square; and Nelson Mandela Place.
Zip file (includes PDF map): 53Mb
Audio length: 43:10 mins
Walking time: 2 hours (approx)
Glasgow highlights
Merchant history
Glasgow found its feet as a trading post, with a particular quarter being dubbed Merchant City. Our tour takes you through its heart, which boasts some glorious Georgian and Victorian architecture, including the Glasgow Savings Bank – now a fashion store, but with its original impressive exterior intact..
Glasgow sons
There are several famous historical figures associated with Glasgow, many of which have strong links to stops on our tour, such as the explorer David Livingstone, celebrated architect Charles Rennie Mackintosh and, from recent memory, Donald Dewar, Scotland’s first-ever First Minister.
Religious endeavours
The city has always had strong religious links, and Glasgow Cathedral itself is one of the city’s iconic highlights. Founded by St Mungo, who later became patron saint of Glasgow, in 550AD, it is one of the few catholic buildings to escape relatively unscathed from the reformation period. The nearby St Mungo Museum of Religious Life and Art celebrates the six major faiths of the world, while in the Merchant City area, you will find Ramshorn Kirk, a Presbyterian church that now operates as a theatre.
Charles Rennie Mackintosh led the Art Nouveau movement in Britain, which brought his love of Japanese design to a wider audience. The recreation of the Willow Tearooms provides an opportunity to see his work up close, and his legacy can also be seen at the nearby Glasgow School of Art. The tour also passes by the Gallery of Modern Art, which has earned a reputation as one of the most visited galleries of its type outside of London.
Provand’s Lordship, ‘the oldest house in Glasgow’, was built in 1471 and, through the efforts of various historians and preservation societies, remains standing for you to explore today. Also on the tour is the Tollbooth Steeple, an impressive tower that once marked the central point of the city.
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‘Thank you so much for the two Canterbury walks — they made our weekend a high quality event! The guides are clear and interesting, and provided many fascinating insights into the history and locations of the town. The walks were an ideal length, and the stopping points were clearly marked on the handy map provided with the download. We loved being allowed to go at our own pace — and we could stop to nip into the shops along the way! We are thinking of where to go for our next weekend break — but we will have to make it one of the towns covered by Tourist Tracks so we know we will have a good time! Thanks again for a top-quality guide at such a low price’
Lewis Kirby
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Bath MP3 Audio Walking Tours | Beverley MP3 Audio Walking Tours | Brighton MP3 Audio Walking Tours | Cambridge MP3 Audio Walking Tours | Canterbury MP3 Audio Walking Tours | Cheltenham MP3 Audio Walking Tours | Edinburgh MP3 Audio Walking Tours | Ely MP3 Audio Walking Tours | Glasgow MP3 Audio Walking Tours | Hull MP3 Audio Walking Tours | London MP3 Audio Walking Tours | Oxford MP3 Audio Walking Tours | Stratford-upon-Avon MP3 Audio Walking Tours | York MP3 Audio Walking Tours |
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Adam Fraser of Inchcoulter died of fever at plantation Kingillie in Berbice in September 1805. Peter Fairbairn, who noted the death in a letter to Lord Seaforth (NAS GD46/17/27), described him as the 'youngest brother of Alex Fraser of Inchcoulter, who is on his way to Grenada'.
Alexander Fraser of Inchcoulter (for family tree see Ancestry: subscription required)
In the late 1790s, Alexander Fraser (17??-1837) was in charge of the Baillie’s plantation Hermitage in Grenada, and was described, at this time, as a ‘planter of experience’. He was probably also a member of the Grenada Council. He had married Evan Baillie’s niece [Emilia Duff of Muirton] ‘some years ago’ and organised contributions from Grenada towards the founding of the Northern Infirmary in Inverness. Fraser’s son, born in Grenada in 1800/01, was named Evan Baillie Fraser (1800-91).
In 1806 Evan Baillie advanced £4500 on behalf of Fraser for the purchase of the Inchcoulter estate (also known as Balconie) in Ross-shire, where Fraser created the village of Evanton and where one of the streets was named Hermitage Street [Douglas Hamilton, p67 & 200; grave stones; Evanton Oral History Project].
By 1807 he was regularly described as ‘late of Grenada’ indicating that he was now resident in the UK. In 1812 Alexander Fraser entered into a partnership with Evan Baillie’s third son, James Evan Baillie, trading as JE Baillie, Fraser & Co of London. This company, dissolved in 1820, consisted of James Evan Baillie, Alexander Fraser, Hugh D Baillie, George H Ames and George Fowler. [London Gazette]
In 1825 Alexander Fraser owned plantation Livera in Grenada - after which another street in Evanton was named. [Slave Registers]. Fraser received compensation for his slaves in Grenada at emancipation.
Gravestone at Kiltearn: In memory/of/ALEXANDER FRASER/of Inchcoulter/died at Balcony March 23rd 1837/and of/EMILIA DUFF/of Muirtown/his wife/died at Balcony Feb. 19th 1839.
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VOCALIST MAGAZINE NETWORK / Home / Home Slider / Around the World New global rules
Around the World New global rules
While parliament’s chief preoccupation is the letter of the law, it also has a duty to uphold the law’s spirit.
That role is especially important in business and finance, where a tension exists between a commerce that wants anything legal to be also acceptable and a broader social conception of economic activity.
Quantitatively, the internet has massively expanded the sheer volume of news items available to one person. The speed of news flow to individuals has also reached a new plateau. This insurmountable flow of news can daunt people and cause information overload.
We can call this period the “technetronic era”, in which “global reality increasingly absorbs the individual, involves him, and even occasionally overwhelms him.”
Online news has also changed the geographic reach of individual news stories, diffusing readership from city-by-city markets to a potentially global audience. Steve Jobs – Apple Worldwide Developers’ Conference, 1997
The importance of social media in news production and news dissemination
Now we look at what a social media strategy could mean for a media organisation.
But first, let’s look at how we got to this stage in media’s development.
The media is in a constant state of change, or at least it should be.
Technological advances, leading to changing audience behaviour, resulting in altered attitudes to consuming and sharing news, which means that a media organisation can’t afford to stand still.
The “broadcast AT or publish AT” model, the “engage with on our terms” model, and the “participate in” model.
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Press Release: Ministers, Others to Engage in Civil Disobedience to Stop NYPD “Stop and Frisk”
Category: Press Releases
FOR IMMEDIATE RELEASE: October 21.2011
Civil Disobedience in Harlem Demands:
STOP NYPD’S STOP & FRISK
Who: Cornel West, Professor, Author, Public Intellectual
Carl Dix, Revolutionary Communist Party
Rev. Stephen Phelps, Interim Senior Minister of Riverside Church
Rev. Earl Kooperkamp, Rector of St. Mary's Episcopal Church
Debra Sweet, Director of World Can't Wait
Rev. Omar Wilks, Unison Pentecostal Church
Prof. Jim Vrettos, John Jay College of Criminal Justice
Elaine Brower, Military Mom and World Can't Wait
Joined by “OCCUPY WALL STREET” & others
When: Friday, October 21
1:00 PM Rally at Harlem State Office Building, 125th St. & Adam Clayton Powell Blvd.
1:30 PM Non-Violent Civil Disobedience at the NYPD 28TH Precinct, West 123rd Street & Frederick Douglass Blvd.
New York, N.Y., October 21, 2011 The NYPD’s notorious program of STOP & FRISK will be the target of a new movement of non-violent civil disobedience tomorrow as professor and author Cornel West and Carl Dix of the Revolutionary Communist Party are joined by the Reverend Stephen Phelps (interim senior minister of Riverside Church) and several other clergy, professors, teachers in front of the 28th NYPD precinct in Harlem to stop what has been documented to be a “racist, illegal, illegitimate and unconstitutional policy.”
Activists to Protest Former Bush Administration Officials for War Crimes & Demand Accountability in New York City
Activists to Protest Former Bush Administration Officials for War Crimes & Demand Accountability in New York City 9/8 &9/9
Stephanie Rugoff, War Criminals Watch, 646-807-3259
Nancy Mancias, CODEPINK, (415) 342-6409
WarCriminalsWatch.org
New York – When former Bush administration officials come to New York to speak, NYC activists from organizations including War Criminals Watch, World Can't Wait, CODEPINK and Witness Against Torture will be ready with outside protests demanding accountability and justice for the lies they told the people and crimes they committed during their time in office. The visual and vibrant protests will take place in various Manhattan locations.
Hudson Union Society – Outside Carnegie Hall, 57th St.
September 8, 2011, 5:00 pm - 6:30 pm
University Club, 1 W. 54th St.
Donald Rumsfeld and Michael Mukasey
Kaufmann Concert Hall,
Lexington Avenue at 92nd St
John Yoo and Michael Chertoff
September 9, 2011, 9:00 am - 4:00 pm
New York Law School,
“These are the people who brought us torture, indefinite detention, and trillion-dollar wars that have claimed countless Afghani, Iraqi and US lives. They should be indicted and prosecuted for their crimes, not honored as speakers and special guests at symposia, memorials and fancy dinners,” said Stephanie Rugoff, coordinator of War Criminals Watch. “People of conscience must insist on accountability for the actions of U.S. officials.”
Demonstrations will continue for the rest of the month when George Bush, Dick Cheney, John Ashcroft, John Negroponte and Henry Kissinger speak at other NYC venues. Press releases on those events will be sent soon.
Supporters of Accused WikiLeaks Source PFC Bradley Manning To Rally Saturday at Times Square, NYC
WHEN: Saturday, June 4tth from 12:30-2:30 pm
WHERE: Times Square Recruitment Center
44th & Broadway
WHAT: Rally to Support PFC. Bradley Manning
New York, NY -- This Saturday, June 4, 2011, supporters of PFC Bradley Manning will converge in New York City and Ft. Leavenworth, Kansas to rally for the soldier who stands accused of leaking classified government information to WikiLeaks and ultimately to the public. Supporters will
rally and march carrying large signs and visuals, calling on government to protect whistleblowers and to drop all charges against Manning.
These will be the first large public rallies to support PFC Bradley Manning since he was transferred to Fort Leavenworth on April 20, 2011, after having suffered extreme confinement conditions at U.S. Marine Corps Base Quantico, Virginia. During the nine months at Quantico, Manning was denied meaningful exercise, social interaction, sunlight and was at times kept completely naked.
Debra Sweet, Director of World Can’t Wait stated, “Bradley Manning is charged with leaking information which, when posted by WikiLeaks, educated the public about how civilians in Iraq and Afghanistan have been victimized by U.S. military occupations. Yet, even though the government admits the video and cables are genuine, the perpetrators of war crimes shown have not been investigated, much less charged with crimes, while Bradley Manning is unjustly charged with making some actions public.”
Last week marked one year since PFC Manning was detained as a suspected source to WikiLeaks, a news organization that receives, reviews and selectively makes public information provided by anonymous whistleblowers. The information that PFC Manning is accused of leaking includes the videotaped massacre of Reuters journalists and Iraqi civilians as well as diplomatic cables that experts believe helped to catalyze democratic revolts across the Middle East this spring. PFC Manning's supporters assert that the information he is accused of revealing should have been in the public domain.
“Bradley Manning's alleged actions are heroic. Instead of being prosecuted, he should be commended for exposing truths about warfare that our military-industrial-corporate complex is trying desperately to conceal from the public,” Veterans For Peace - NYC Chapter 34
“Private First Class Bradley E. Manning, 23-years-old, was arrested in Iraq one year ago on May 26, 2010. He still awaits his first public court hearing, now expected to begin later this summer. Over 4,300 individuals have contributed $333,000 towards PFC Manning’s legal fees and related public education efforts,” Bradley Manning Support Network.
Anti-Torture Protesters Say “Torture Lawyer” Not Fit to Teach Law
Contact: Linda Jacobs (415) 424-7358
This email address is being protected from spambots. You need JavaScript enabled to view it. sfbaycantwait.org worldcantwait.org firejohnyoo.org
ATTN: Daybook/News Desk
PHOTO OPS: Protesters, Graduates Denounce Torture
Protest Demonstration: FIRE, DISBAR and PROSECUTE JOHN YOO
9:00-10:00 AM Outside Hearst Greek Theater, Gayley Road, UC Berkeley
12 Noon to 1:30 Outside Boalt Hall during the Reception
For a fourth year, the UC Berkeley Law (Boalt Hall) commencement ceremony will be the site of protest initiated by the national organization World Can’t Wait and other anti-torture organizations, lawyers, and activists.
World Can’t Wait organizer Stephanie Tang said yesterday: “Boalt harbors a known war criminal on its faculty, and the University of California leadership as a whole is responsible for this total breech of academic and ethical responsibilities to its students and to the public. On Friday we’ll greet the graduates, inviting them all to join the fight to end America’s torture program, and end UC and Boalt’s complicity with it.”
Yoo was a tenured Boalt professor on sabbatical when he worked as a key legal architect for the Bush-Cheney administration, designing illegal torture policies and practices (.e.g, Guantanamo, Abu Ghraib). Most recently he has been in the media spotlight calling the death of Osama bin Laden proof that America’s torture program “worked.” Since January 2010, UC and Boalt officials have assigned Yoo’s classes to secret campus locations to avoid unwanted attention.
A national campaign by legal, activist, and religious organizations has for several years called for the officials dubbed “The Bush Torture Team” to face prosecution for designing and ordering torture, a war crime. Frequent protests and arrests in the Bay Area and elsewhere continue whenever Yoo or other Bush-Cheney team members appear publicly.
“We speak out because justice and the law mean nothing if the torturers walk free, enjoying academic respectability and public celebrity while their victims go unheard,” said Curt Wechsler, editor of FireJohnYoo.org.
Artists, Scholars, Writers Gather to Discuss "U.S. Empire, Islamic Fundamentalism: Both Deadly. Is There Another Way?"
worldcantwait.net
Contact: Debra Sweet
718 809 3803
Discussion of Alternatives to Both U.S. Intervention and Islamic Fundamentalism
What: Artists, Scholars, Writers Gather to Discuss "U.S. Empire, Islamic Fundamentalism: Both Deadly. Is There Another Way?"
Where: Tishman Auditorium, The New School, 66 W. 12th Street, New York City
When: Wednesday, April 27 6:30 pm
Iraqi artist Wafaa Bilal, NYU professor Sinan Antoon, Laura Lee Schmidt of the Platypus Affiliated Society, Revolution writer Sunsara Taylor, and Gregory Wilpert will speak at The New School in New York City on their views of what people of conscience should do in response to the state and direction of the world. The event, on Wednesday, April 27, is co-sponsored by the Platypus Affiliated Society and World Can't Wait, is free and open to the public.
Speakers will address the need to oppose both the U.S. government's claim of the right to militarily intervene in any country in the Middle East, Central Asia and Africa as well as to oppose Islamic fundamentalism and theocracy.
Debra Sweet, Director of World Can't Wait and organizer of the event, states, "Is there an alternative to both empire and Islamic fundamentalism? At a time when the uprisings in the Middle East have given renewed hope to many, there is a chance to break through this impasse and to explore, debate and frame the possibilities of a different way, adding to the urgently needed political oxygen that the peoples of Egypt, Tunisia, and elsewhere have injected into the atmosphere."
Main Media Press & Press Releases Press Releases
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WWJ News
The Warehouses
The Employment Structure
The Chicago Distribution Hub
Join WWJ
Mapping Amazon's Logistics Network
By Olivia LaVecchia
Amazon’s been expanding its infrastructure at a breakneck pace. Between the summer of 2015 and the summer of 2016, Amazon’s network of distribution facilities doubled in number, as it rolled out 14 of its massive fulfillment centers, 11 new sortation centers, and 60 smaller facilities like delivery stations and Prime Now hubs. In July, the company announced that it would have 18 more new fulfillment centers up and running by the end of September. “It’s the biggest expansion of any distribution system for any retailer that we’ve ever seen,” says Mark Meinster, the executive director of a worker center based in the Chicago area.
Many of the facilities have been financed partly by taxpayers. Amazon has pocketed at least $613 million in public subsidies for its fulfillment facilities since 2005, our new report finds, and more than half of the 77 large facilities it built between 2005 and 2014 have been subsidized by taxpayers.
Read More at the Institute for Local Self Reliance (ILSR)
WWJ News from 2016 and before can be read here:
OLDER WWJ NEWS
© 2017 Warehouse Workers Justice Center
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cindy raymond • craig roberton • duke snyder • federal bureau of investigation (fbi) • fraud, lie, deceit, misrepresentation • gabriel "gabe" cazares • gerald bennett wolfe • gordon cook • gregory willardson • henning heldt • jane kember • legal • mary sue (whipp) hubbard • mitchell hermann (also, "mike cooper") • office of special affairs (osa) (formerly, guardian's office) • operation snow white • patrick mcmahon • raymond banoun • richard "dick" weigand • ronald j. schultz • salary • slave labor • space opera • tax matter • william w. "bill" franks
Church of Scientology reorganizing — St. Petersburg Times (Florida)
Author(s): Craig Roberton
Tag(s): Church of Scientology Flag Service Organization (CSFSO) • Church of Scientology International (CSI) • Church of Scientology of California (CSC) • Craig Roberton • Fort Harrison Hotel (also, Flag Land Base) @ 210 South Fort Harrison Avenue Clearwater FL United States • Laura Wolfe • Operation Snow White • Phillip Park • Real estate • Ronald J. Schultz • St. Petersburg Times (Florida) • Tax matter • William W. "Bill" Franks
7 Scientologists drop appeals, face jail terms — St. Petersburg Times (Florida)
More: news.google.com
Author(s): Patrick McMahon
Tag(s): Cindy Raymond • Duke Snyder • Federal Bureau of Investigation (FBI) • Gabriel "Gabe" Cazares • Gerald Bennett Wolfe • Greg Taylor • Gregory Willardson • Henning Heldt • Jane Kember • Judge Charles R. Richey • Legal • Mary Sue (Whipp) Hubbard • Mitchell Hermann (also, "Mike Cooper") • Morrison J. "Mo" Budlong • Operation Snow White • Patrick McMahon • Raymond Banoun • Richard "Dick" Weigand • Sharon Thomas • St. Petersburg Times (Florida)
Court upholds convictions of 9 Scientologists — St. Petersburg Times (Florida)
Tag(s): Cindy Raymond • Duke Snyder • Federal Bureau of Investigation (FBI) • Gerald Bennett Wolfe • Gregory Willardson • Henning Heldt • Legal • Mary Sue (Whipp) Hubbard • Mitchell Hermann (also, "Mike Cooper") • Operation Snow White • Patrick McMahon • Raymond Banoun • Richard "Dick" Weigand • St. Petersburg Times (Florida)
Shake-up of Scientology agency told — Los Angeles Times (California)
More: pqasb.pqarchiver.com
Author(s): John Dart
Source: Los Angeles Times (California)
Tag(s): Doug Smith • Geoffrey Miller • Gordon Cook • Jane Kember • John Dart • Los Angeles Times (California) • Mary Sue (Whipp) Hubbard • Office of Special Affairs (OSA) (formerly, Guardian's Office) • Operation Snow White • William W. "Bill" Franks
Top Scientology officials removed from Church — New York Times
Source: New York Times
Tag(s): Gordon Cook • Laurie Zurn • Mary Sue (Whipp) Hubbard • New York Times • Office of Special Affairs (OSA) (formerly, Guardian's Office) • Operation Snow White • William W. "Bill" Franks
Curb Scientology with ordinances, lawyer suggests — Clearwater Times (Florida)
Source: Clearwater Times (Florida)
Tag(s): Anthony Shoemaker • Clearwater Times (Florida) • Craig Roberton • Fraud, lie, deceit, misrepresentation • James "Jim" Calderbank • Kenneth J. Whitman • Mary Sue (Whipp) Hubbard • Michael J. Flynn • Office of Special Affairs (OSA) (formerly, Guardian's Office) • Operation Snow White • Ronald J. Schultz • Tax matter
Scientology: The sickness spreads — Reader's Digest
Author(s): Eugene H. Methvin
Source: Reader's Digest
Eighteen months ago, the U.S.-based Church of Scientology launched a global—and unsuccessful—campaign to prevent publication of a Reader's Digest report called "Scientology: Anatomy of a Frightening Cult." The church engaged a detective agency to investigate the author, Digest Senior Editor Eugene H. Methvin. Digest offices in a half-dozen nations were picketed or bombarded with nuisance phone calls. In Denmark, South Africa and Australia, the church sued unsuccessfully to prevent publication. In the months since the article appeared, in May 1980, a ...
Tag(s): A History of Man (book) • Alan Wilson • Andrew Orsini • Apple Schools • Association for Better Living and Education (ABLE) (formerly, "Social Coordination" or SOCO) • Boston Globe • Commissions • Cost • Dead agenting (Black PR, smear campaign) • Detox • Dianetics: The Modern Science of Mental Health (book) • Eugene H. Methvin • France • Fraud, lie, deceit, misrepresentation • Front groups • Gabriel "Gabe" Cazares • Germany • Idaho • Income • Infiltration • Jane Kember • Lawsuit • Lorna Levett • Los Angeles Times (California) • Mary Sue (Whipp) Hubbard • Medical claims • Michigan • Narconon (aka Scientology drug rehab) • Office of Special Affairs (OSA) (formerly, Guardian's Office) • Operating Thetan (OT) • Operation Snow White • Public funding • Raymond Banoun • Reader's Digest • Recruitment • Rodolfo Zucca • Salary • Silencing criticism, censorship • Slave labor • Space opera • St. Louis Post-Dispatch • St. Petersburg Times (Florida) • Suicide • Union Nationale des Associations de Défense des Familles et de l'Individu (UNADFI) • Vibeke Damman • Yves Lecerf
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Early UW-Texas Q&A
Posted on June 1, 2012 by Robert Gagliardi
We’re three months away from Wyoming’s season-opener at Texas, but it’s never too early to talk college football.
Carter Strickland from ESPN asked me this week to answer five questions about Wyoming, so I asked him to answer five questions for me about Texas. So here it is. We start with my questions and his answers, followed by my answers to his questions. Be sure to follow Strickland on Twitter: @espnstrickland
Hope you enjoy it, and hope to hear your thoughts and opinions.
Texas returns one of the better defenses in the country. What are those strengths and are there some possible weaknesses Wyoming could exploit?Texas was the 11th in the country in overall defense last year and for a five-game stretch late in the season the only two defenses that were more productive were LSU and Alabama. The issue for Wyoming is that Texas is faster on defense this year and has much more depth across the line. The Longhorns added junior college transfer Brandon Moore as well as the top defensive tackle in the country Malcom Brown to the roster. They will go 10-deep across the line with both defensive ends, Alex Okafor and Jackson Jeffcoat, being for sure NFL players in 2013.
The spot where Wyoming might be able to exploit Texas is at linebacker. Texas has two first time starters in Steve Edmond and Demarco Cobbs. While both have very good upside, they are not used to all the schemes called by defensive coordinator Manny Diaz. This could cause them to get out of their lanes every once in a while and if that happens, Wyoming needs to exploit it.
The secondary is very tough and returns three of four starters, including two corners, Carrington Byndom and Quandre Diggs, who are considered two of the best in the Big 12.
Will running the ball be this team’s identity this season, and how much do you think the passing game will improve? Texas wants to run the ball 60 percent of the time and has the tailbacks to do it. The Longhorns signed the No. 1 tailback in the country, Johnathan Gray, with the 2012 class. This came after they signed the No. 2 tailback in the country, Malcolm Brown, in 2011. Add to that Joe Bergeron, a back many consider better than Brown, and Texas will use a trio of guys to pound the ball.
The passing game is still in flux. Quarterback David Ash is coming off a terrible freshman season. He completed less than 60 percent of his passes and threw untimely interceptions. Don’t look for the offense to use the deep ball with him every often. There are going to be a lot of passes out to the flat and underneath. Texas does have receives who can make some moves when they are in space. But, right now, they are not a deep threat offense.
If you’re Wyoming’s offensive and defensive coordinators, who are the guys they need to be aware of on both sides of the ball? Marquise Goodwin is the one to watch on offense. The wide receiver is one of the fastest players in college football. (He is an Olympic hopeful in the long jump.) He also has very good hands and is tenacious when going up to get the ball. Texas wants to let him operate in some space this season so watch out for bubble screens to him.
On defense, safety Kenny Vaccaro runs the show. The senior seriously considered declaring for the draft last season and probably would have been a third round pick. He is more than peeved with himself for not sticking with his instincts and declaring. That means he is playing with a huge chip on his shoulder this year.
If you were to game plan for Texas, what would be the biggest keys on offense and defense for Wyoming? Somehow they have to get pressure on David Ash. He does not do well with quick decision making. So if the defensive line can pinch him in from the outside and force him to make quick throws over the middle, Wyoming might be poised to pick off a couple of passes.
On the offensive side of the ball there needs to be a ton of play fakes and misdirection plays. Texas is gong to come screaming at the ball every time. So if Wyoming can just force a slight hesitation they might be able to get some yardage.
Do you think there’s a chance for an upset, and what’s your early prediction for the final score? Texas starts very slowly and the last two years at home have not been very good ones. Rice hung around in the first half last year and BYU nearly beat Texas at home. I think it will be close early and ugly late. I say Texas by at least three touchdowns simply because the Horns have the depth to wear Wyoming down in the second half. Plus after two seasons of mediocrity they are not going to show any mercy to an opponent if they feel they can run up the score.
Texas was mediocre at best in passing offense last season so with that in mind just how good is the Wyoming’s pass defense? Are there some studs that stick out there who can change the game with a pick or a sack? Wyoming’s pass defense has a chance to be good, especially with the guys it has in the secondary. The Cowboys have one of the better cornerback duos in the Mountain West in sophomore Blair Burns (Plano) and junior Marqueston Huff (Texarkana). Burns earned three different Freshman All-America honors last season and led the team with four interceptions. Huff had three interceptions and was tops on the team with three fumble recoveries, two of which he returned for touchdowns. At safety, there is senior Luke Ruff, a preseason All-Mountain West candidate and pretty much the leader of the secondary – and the defense in general. Sophomore safety Mark Nzeocha played outside linebacker last season and was moved to safety in the spring. He’s one of five players on the team from Germany, and he’s a beast at 6-3, 220 pounds. He really took to playing safety in the spring and could make things happen there. There also is some good depth in the secondary, although it’s young with sophomore cornerbacks DeAndre Jones (Killeen) and Darrenn White, and sophomore safety Chad Reese (Tyler). Senior Luke Anderson (Southlake) is the top nickel back and senior Kenny Browder (Round Rock) has played safety and corner during his career. Wyoming should be more athletic at linebacker with seniors Korey Jones and Oliver Schober. The line is a bit thin on numbers and production, but it has a good one in the middle in senior defensive tackle Mike Purcell (6-3, 303 But some newcomers will need to help along the line.
Let’s stay on the defensive side of the ball and talk about rush defense. The Longhorns are most likely going to run the ball on 60-plus percent of their plays. The hope is to wear down the opponent. How deep is Wyoming across the front four and how good are the linebackers? Wyoming allowed 232 rushing yards per game last season, but survived that for the most part by forcing 31 turnovers (13 interceptions, 18 fumble recoveries). With some uncertainty along the line, this remains a big concern heading into the season. Wyoming runs a 4-3 base but will show multiple looks. New defensive coordinator Chris Tormey likes to disguise coverages and looks to cause confusion. The Cowboys may need to rely on more of that if the defensive line struggles to progress.
Over on the offensive side of the ball what is Wyoming’s big-play capability.? Who are the threats? The big-play threats on offense starts with sophomore quarterback Brett Smith, the reigning Mountain West Freshman of the Year. He completed 61 percent of his passes for 2,622 yards with 20 touchdowns and 11 interceptions, and led the team in rushing with 710 yards and 10 touchdowns. He also caught a TD pass. For a youngster he’s incredibly poised and mature, and the offense will go as far as he goes. Wyoming returns its three leading receivers from last year in terms of catches in sophomore Dominic Rufran, junior Robert Herron and senior Chris McNeill. Herron is one of the faster guys on the team, and needs to become more of a big-play guy in the passing game. Wyoming also is high on sophomore receiver Trey Norman (Texarkana), who had a good spring. Yet another Texas product, sophomore running back Kody Sutton (Texarkana) is just 5-8 and around 200 pounds, but is fast and showed some good things late in the season. Junior Brandon Miller can play both running back and receiver.
Channel your inner bookie and give me a line that you think would be reasonable for this game and why? I think Texas by two touchdowns, mostly because it’s Texas vs. Wyoming if you know what I mean. It’s at Texas and not a lot of people, let alone bookies, won’t give Wyoming much of a chance. Despite Texas’ struggles recently it still is loaded with talent and with this being early in the year in Austin, I see the Longhorns being a heavy favorite.
Finally, what would it take for an upset to occur? Is it beyond the realm of possibility? Or is it plausible? Wyoming can’t let Texas run the ball 60-plus times and wear it down as you stated earlier. The defense must get off the field and make some stops. It also needs to force at least two turnovers and give its offense good scoring chances on Texas’ side of the field. If the Cowboys can be efficient on offense and force some turnovers on defense, it could be an interesting game on Sept. 1. I think an upset is possible, but still a long shot.
This entry was posted in Football and tagged Alex Okafor, Blair Burns, Brandon Miller, Brandon Moore, Brett Smith, Carrington Byndom, Carter Strickland, Chad Reese, Chris McNeill, Chris Tormey, Darrenn White, David Ash, DeAndre Jones, Demarco Cobbs, Dominic Rufran, ESPN, Jackson Jeffcoat, Jonathan Gray, Kenny Browder, Kenny Vaccaro, Kody Sutton, Korey Jones, Luke Anderson, Luke Ruff, Malcom Brown, Manny Diaz, Mark Nzeocha, Marqueston Huff, Marquise Goodwin, Mike Purcell, Quandre Diggs, Robert Herron, Steve Edmond, Texas, Trey Norman, Wyoming by Robert Gagliardi. Bookmark the permalink.
7 thoughts on “Early UW-Texas Q&A”
Travis Herold on June 1, 2012 at 2:04 pm said:
I’m honestly just hoping to escape Texas with as few injuries as possible. Don’t care what the final score is.
Nick on June 1, 2012 at 10:50 pm said:
Good write up! The Pokes Dline must come up big or Texas will grind on us till the catch us cheating up on em and pass for the TD’s. If we run a lot of 3 man front and can get our backers to make some tackles for loss we will be in this game.
Timmy Jack on June 2, 2012 at 3:19 pm said:
Will be in Austin for the 3rd round of Christensen inspired Cowboy-Longhorns pigskin. 2 years ago it was unbelievably hot… we didn’t get much accomplished other than get roasted. The tent party pregame was sweet, Jim Brandenberg and his daughter showed up, that was nice. But, if we are ever going to get over the hump and get some recognition, we need a major upset. This is a perfect spot for us to make a statement. I’ve traveled the last decade to some big games, only to watch us unravel- early and often. Somehow I remain optimistic that one of these games a truly brilliant upset will occur; I can’t afford to miss this marquis game….So, with my last breath I remain true to the core that Cowboy Football will rise like a Phoenix in the hot Texas sun and burn the faithful UT boys in a shoot-out. Go Pokes.
Brian on June 3, 2012 at 9:24 pm said:
That is spot on! WYO needs to win a game like this or keep it really close. The give em hell for a half is over, no we need to make a presence and statement that the Pokes are here, and taking the MW like we should!
Mc on June 3, 2012 at 7:12 pm said:
I will not attend this time, cuts into some of the last premium weather days for golf. Hope its on TV, otherwise I guess I’ll read about it in the paper.
Kyle on June 4, 2012 at 8:25 am said:
Good write up Gags and Carter. Hope for our Boys’ there isn’t another tropical storm this time, 105 with humidity is brutal. Texas consistently has top talent in country but has underperformed the past two seasons. Hopefully the longshot happens. Either way Austin will be a blast as 6th street and the Salt Lick don’t disappoint.
rgagliardi on June 4, 2012 at 12:01 pm said:
Thanks for the kind words, Kyle.
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Tetiaroa - the ecology of Marlon Brando's paradise island
After my visit to Moorea in French Polynesia, I spent a spellbinding day and night at Tetiaroa. Tetiaroa (Tahitian for "far in the ocean") is a coral atoll sitting north of Tahiti and Moorea, a Tahitian "leh" (garland) of tree-wreathed coral sand islands (“motus”) wrapped round a turquoise lagoon. This is probably as close to an apparent archetypal tropical island paradise as it is possible to imagine. The archipelago was inhabited by Polynesians for many centuries, and was a retreat for Tahitian royalty. As elsewhere, its population went into decline following European contact, and it was sold by the Tahitian king to his American dentist a century ago. He converted the vegetation of many of the motus to dense coconut plantations for the production of copra from the fibres, but these were abandoned a few decades later as the copra market went into decline. The dentist’s daughter then lived almost alone on the atoll into her old age.
In the 1960s Marlon Brando, at the peak of his Holywood stardom, came upon the islands while looking for sets for the filming of Mutiny on the Bounty. He was bewitched by the place and bought the entire archipelago. He visited it often as a retreat from the world of Holywood, and also set up a basic hotel on one motu. But is his later decades the hotel struggled to survive and the island went into slow neglect, while also avoiding the expansive development of many other Polynesian atolls. Soon after Marlo Brando’s death, the atoll was bought up by a very high-end eco-resort, the Brando, which has established an aesthetically and environmentally discrete hotel on the south-western motu, Onetahi that has won a Platinum LEED (Leadership in Energy and Environmental Design) award.
Thus, by historical circumstances Teriatoa offers a chance to study a coral atoll with a modest contemporary human footprint, but one which faces many of the legacies issues and future challenges faced by many Pacific atolls (see below). I have been invited to look at the potential for terrestrial ecosystems science at Tetiaroa. My host is the Tetiaroa Society, a non-profit environmental organisation that manages conservation and scientific research in the atoll in collaboration with the hotel.
We journeyed at dawn by dinghy from Moorea to Tetiaroa, a bumpy journey of 2.5 hours. It’s a short journey, but halfway through in a small dinghy I gained a huge sense for the vastness of of the Pacific, and respect for the Polynesian navigators who made this vast ocean and its ever-shifting swells their home. Soon after we sighted the motus of Tetiaroa as thin slivers of trees on the horizon. As we approach we were greeted by a young humpback whale joyfully breaching clear of the water, followed soon after by an encounter with a mother and child humpbacks, and a host of spinner dolphins buzzing our boat. The waters of the lagoon are higher than the surrounding ocean, filled by waves crashing against the surrounding reef, so we had to navigate a precarious cascade to work our way into the light turquoise waters of the lagoon and dock on a sandy beach. Black tipped reef sharks, striking but only a metre in length, circled curiously as we waded on shore. We stayed at the Ecostation, a comfortable research facility with excellent labs within the hotel grounds.
There is a fair amount of marine research occurring on Tetiaroa, but almost nothing on the terrestrial ecosystems. One of the downsides of being an ecologist is that we know too well that there is often trouble in paradise (beware of taking an ecologist on honeymoon!). Most tropical islands hold a legacy of extinction and invasion - the extinction of over a thousand species of birds in the Pacific following human settlement was probably the biggest extinction event of the Holocene.
There are two main current terrestrial environmental issues on the atoll: the challenge of of rat invasion, and the legacy of the dense coconut plantation. To a holiday visitor the white sandy beach lined by dense groves of coconuts is archetypal paradise. Indeed, the Polynesians found a multitude of uses for the coconut and it is an indispensible part of the cultural heritage of the Pacific islands. But this is an ecosystem out of kilter. The coconut groves, especially if untended, form dense stands with fallen palm fronds suppressing regeneration by other plant species, and providing a poor habitat for nesting birds. It is debatable whether coconut was naturally found in Polynesia, or was brought by the Polynesians. But dense coconut stands are a legacy of copra plantation. There are two species of rat on the atoll, the smaller Polynesian rat or kiore (Rattus exulans), which arrived with the first Polynesian settlers (deliberately - it was regarded as a luxury food), and the black rat (Rattus rattus), which arrived after European contact. Both rats negatively affect the ecosystem but the larger black rat is particularly problematic, by eating up seeds and preventing new plant recruitment, and by raiding nests and eating young chicks. They also feed off the plentiful coconuts, which results in a large and active rat population. Hence there is an ecological meltdown, with dense coconut stands reducing bird habitat and support an large rat population, and the rat population suppressing plant diversity and consuming young birds. Land birds are long gone. And as sea birds now largely avoid the most rat-abundant islands, the inflow of nutrients from ocean to land through bird guano is greatly reduced.
I visited with James Russell of Auckland University (see his National Geographic blog here), who hopes to implement a rat eradication effort on some of the motus, and others are also thinking of reducing coconut abundance in some areas. A key ecological question here is: “can we restore plant and animal diversity and ecosystem nutrient cycling function here by removing rates and/or reducing coconut abundance?”. To do this we are contemplating arranging an array of small ecosystem monitoring plots across various motus, covering a range of invasion and disturbance histories. The spatial patterns across these motus now will be interesting in themselves, but they plots would also provide a baseline for future experiments with rat eradication or coconut thinning.
A different, longer-term question is climate change: how will these low-lying atolls cope with sea level rise? Will the rate of coral aggradation and motu deposition be sufficient to keep up with the rising seas, and how will vegetation and biodiversity respond to these shifts? Again, establishing a baseline plot network now could provide valuable insights into how these ecosystems cope, and what interventions might help.
Moorea, French Polynesia
Last week I visited the Pacific island of Moorea, which sits just next to Tahiti in the Society Islands, in French Polynesia, an array of islands widely scattered across the Central Pacific. The islands form a progression of volcanic seamounts, with youngest in the south-east peaking in the 2100 m peaks of Tahiti, and the oldest in the north-west subsiding into perfect coral atolls. My host was Neil Davies, Director of the Gump Research Station in Moorea, and I am here to discover a little more about the forests of Polynesia, to find ways of supporting and devleoping some of the forest research here, and to bring in some of the ecosystem process studies that we do elsewhere across the tropics, with the potential of bring some of these forests into our Global Ecosystems Monitoring Network. Moorea is the focus of the IDEA Digital Avatar project, and effort to digitise an entire island ecosystem from 'genes to satellites'. There is an article about this project in Nature. As a result the biodiversity of the land and marine ecosystems in Moorea is particularly well catalogued.
The landscapes of Tahiti and Moorea (and many other Pacific volcano islands) are truly breath-taking, with the basalt volcanoes eroding way into almost vertical-sided mountains and towers, some of the most astounding topography I have seen anywhere. As Darwin noted when stopping at Tahiti after his explorations of South America: “in the Cordillera, I have seen mountains on a far grander scale, but for abruptness, nothing at all comparable with this". The high mountains hold on to native cloud forest and rocky scrub, but the lower levels are a lush green mosaic of invasive species, farms and light green fernlands. The islands are surrounded by a skirt of coral reef holding in a lagoon of perfect turquoise waters.
In between meetings and visiting the forest and lagoon, I tried and absorb all I could about this mesmerising land I found myself in and knew so little about. My sources on the geology and vegetation history were “Vegetation of the Tropical Pacific Islands” by Dieter Mueller-Dombois and Raymond Fosberg. I also borrowed off Neil an excellent biography of James Cook by Frank McLynn, and read particularly closely the descriptions of Cook’s several contacts with Tahiti and the societies he found there, and how both reacted to the “other” in this collision of worlds. A highly recommended book that highlights how astonishing both Cook and the Polynesian societies were, and captures the astonishing nature of the first contacts.
We visit the Opunohu valley, a lush mosaics of forests, farmlands, archaeological remains. This area was densely populated and farmed at the time of European contact, and suffered a population crash and almost complete depopulation over the 18th and 19th centuries. Feral chickens, first brought over by the Polynesians, run wild over the landscape, itself almost entirely free of predators. The mapae are rectangular stone enclosures that were used for religious ceremonies, and are now groves of Tahitian chestnut trees (Inocarpus fagifer) with wonderful fluted buttress roots.
Some of the key trees that may have been brought by the Polynesians or that may be native include Hibiscus tiliaceus, Pandanus tectonis, Casuarina equisetifolia. As in many islands, the main environmental story is one of biological invasion, Big invasive species here include Tecoma stands, Psidium cattleianum (strawberry guava) and most recently, the all-smothering Miconia calvescens.
The view from Moorea is of an ocean planet. Polynesia sits in the middle of a hemisphere that is probably over 95% ocean, with what continental area there is is ringing its fringes, and scattered throughout this planet-sized ocean are small islands that are legacies of volcanic hotspots. Every wave of “discovery” of these is an astounding tale. First the various species of plant, bird and insect that manage to make it across thousands of miles, often by accident, to stumble on an island refuge. There they slowly specialise and diverge and take advantage of this new ecosystem that they build. Then the human discovery, an amazing tale of Polynesian adventures reading the stars, winds and swells to cross vast distances and create unique cultures. Then the Europeans, with adventurers such as Cook and his sailors expanding the known world with their exploration of a new ocean world and civilization. Each "discovery" has been accompanied by ecosystem disruption and loss, as well as the creation of something new.
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The Ingredients Of A Great Book
SHE CAN TELL A STORY,. BUT CAN SHE WRITE A SENTENCE?
One of the best posts I've read on the internet for ages is Sarah Ditum's "Y'know, for kids", looking at the mixed critical response to JK Rowling's new adult book, The Casual Vacancy. While the entire article, which is about the perception that "Things intended for and marketed to adults" are better than those for children, is a fabulous read, one sentence particularly stood out. "Sure, Rowling can tell a story, said Anthony McGowan on the Today Programme yesterday, but can she really write a sentence? – as if plotting were some low-rent trick and the real artists of literature were putting more effort into crafting their gem-like and subtly revealing descriptions of kitchen tables."
THE MOST IMPORTANT THING IS...
It got me thinking - what IS the most important part of a novel for me? Does the plot outweigh the prose? Where do the voice, the characters, the dialogue and the location fit in? I've just started The Casual Vacancy myself. I'm hooked, but can see where McGowan's coming from - I'm not finding the prose to be anything special. However, I'm really enjoying it because the characters are so wonderful, and I think that's always been Rowling's strongest point for me. In the Harry Potter series, I thought that Snape, Neville, Luna, and several others were absolutely wonderful, alongside the main trio, of course, and I was desperate to find out what happened to everyone. Add in a great grasp of plotting, and it's easy to see why the books have thrilled so many readers.
I decided to try and break things down and identify a few books which I think are particularly good at each of these aspects, and work out my own personal order of importance.
When I took to Twitter and asked for people's opinions on this topic, Annabelle from Read Write And Read Some More said "Great characters make the story and make the reader more engaged and involved. We root for them to win" and Anna Scott of Anna Scott Jots said "If I can't engage with the characters, then it's a deal breaker for me, no matter how clever the plot." I'd agree with both - I have to find at least some of the characters really likeable, and worth rooting for. For me, that's the key thing.
Examples: Pushing The Limits by Katie McGarry - I'm absolutely thrilled that I've got a mini-interview with Katie on supporting characters later this week, because I think Pushing The Limits has got some of the best supporting characters I've read in years. They're all brilliantly described, with their own realistic motivations and everything they do seems to follow on from this.
The Monstrumologist series by Rick Yancey - I'm hoping to write a guest post for Word For Teens on the title character from this stunning series, so will keep my praise brief here. Dr Pellinore Warthrop is surely one of the greatest creations of the last decade, a brilliant but egotistical man who has a fierce drive to fight against the monsters he sees but is prone to overconfidence which can be dangerous. Narrator Will Henry, Warthrop's young apprentice, is just as brilliantly portrayed, and the dynamic between the pair is superb.
The Dragon's Path series by Daniel Abraham - Sneaking an adult fantasy in here because I can't resist plugging it wherever possible. Abraham's epic fantasy series is wonderful because it has so many characters who appear to be archetypes - a renowned hero jaded by fighting, a court baron protecting his king, a studious young son of a noble house and an orphaned girl disguising herself as a boy - but Abraham plays with convention and none of them are what you'd expect.
For me, a really strong voice can make an otherwise average book worth reading, or push an otherwise good book to 'must read' status. I think the books with a great narrative voice tend to stay with me a long time, as well. YA author Nansi Kunze makes a case for this being the most important element, saying "That's a tough one! I'm going to go for voice, though. It's what really makes an MS unique (& stand out from the slush pile!)."
Examples: Big Woo by Susie Day - I generally think 'less is more' when you're doing internet speak, and quotes like "eeeee sekrit crush" and "Neverneedinganumbrellagirl to the rescue" would usually have me slamming the book shut. They didn't, in this case, because the voice of the book is absolutely perfect. Serafina is a wonderful character who Susie has brought to life brilliantly, and the lolspeak and so on are completely right for her.
The Anti-Prom by Abby McDonald - I picked this one up just by chance, because I thought it sounded fun. I was completely blown away by it because McDonald captures the three voices of her trio of narrators so beautifully. Bad girl Jolene, popular Bliss, and near-invisible Meg are all superb here.
Gossip Girl by Cecily Von Ziegesar - CVZ gets away with fairly weak characters in the first few books of this series because of the snarky narration which practically drips with money. From the early line "Our **** still stinks but you can't smell it because the bathroom is sprayed hourly by the maid with a refreshing scent made exclusively for us by French perfumers" right until the end, I devoured this one.
PLOT/STORY
This is the next most important thing for me. Live Otherwise said on Twitter that this was the most important because it's "Rare that you can have any of the others worth spending time with without that." I can think of a few with plots I'd describe as so-so but characters than are so fabulous I'd read them again and again, but for the most part I agree this is really important.
Examples: Harry Potter series by JK Rowling - I loved the last book, in particular, because it answered all of the questions and tied up all of the loose ends without ever feeling like it was JUST doing that. Looking back to the earlier books I was stunned by how far in advance JKR had plotted stuff.
The Bonehill Curse by Jon Mayhew - Any of Mayhew's loosely-linked Victorian trilogy could fit in here, as his plots are always fiendishly brilliant. This is my favourite, though, as it's unpredictable, has great action scenes, and a superb ending.
Billie Templar's War by Ellie Irving - Irving follows up the really good For The Record with an even better sophomore novel here. The story of Billie, trying to create a military tattoo to attract the Queen to her village so Billie can ask her to bring Billie's dad back from the war, is fabulous, and the ending is perfect.
I have to be honest, I very rarely get drawn into a book by the prose. I'm much more interested in the people in it and the plot. On the rare occasions I do find the prose in a book particlarly brilliant, though, it does tend to stick in my mind really firmly.
Examples: The Sky Is Everywhere by Jandy Nelson - WOW. I cried my eyes out reading this. Partly that's down to the wonderful storyline and characters, but it's helped by the superb writing.
Graffiti Moon by Cath Crowley - Gorgeous, gorgeous, GORGEOUS! The most lyrical YA book I've read for ages - possibly ever.
The Great Gatsby by F Scott Fitzgerald - Another adult one. It has three of my favourite quotes of all time, with the last paragraph being perhaps the greatest paragraph ever written, at least in my opinion.
Setting, for me, isn't particularly important normally. If the above elements are weak, a great setting would still never really interest me. If all of the above elements are strong, though, a particularly good setting CAN lift something onto my 'favourites' list.
Examples: A Witch in Winter by Ruth Warburton - A brilliant book (as is sequel A Witch in Love) - with a stunningly described setting in Winter. Warburton captures this British coastal town - the kind of place where people whose parents had been in the village for half a century would still be described as 'offcomers' - wonderfully.
Wereworld by Curtis Jobling - The best fantasy world for ages, Lyssia is an example of stunning world-building. Both in the creation of the Werelords and the political intrigue in the Seven Kingdoms, Jobling has done an outstanding job.
Paper Towns by John Green - If high school is in a world of its own in many ways, the last few weeks of high school are on another planet. Green is pitch perfect in capturing the unique atmosphere of this time in his third book.
In the end, though, the very best books have all of these ingredients. Author Ruth Warburton perhaps summed it up best by saying "if one element isn't working, it ruins the lot. It's like a cake." Clarifying, she said "obviously writers usually have strengths in one or more areas but if one element is really truly absent/appalling then you notice it to the exclusion of all the virtues, in my opinion."
What do you think? What's the most important element to you? Are there any other ingredients of a wonderful novel that I've missed? Let me know in the comments!
Anna Scott 12 October 2012 at 03:01
I've been wanting to read Pushing the Limits for a while and really must push it further up my TBR list!
RE: prose - if all the other elements are in place, I think great prose can push it into all-time favourite reads territory, but without engaging characters and plots etc, good prose could have the opposite and highlight these flaws to an even greater extent.
Great post - very thought-provoking - thanks!
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Sunday Spotlight: Book Review of The Diviners by L...
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UK Giveaway: 3 YA Paranormal Books
Sunday Spotlight: Book Review of Dark Eyes by Will...
What's Wrong With NaNoWriMo?
Mini-Interview: Katie McGarry on Supporting Charac...
Thursday Thoughts: Book Review of Really Weird Rem...
Waiting On Wednesday: Colony East by Scott Cramer ...
Martha Payne, Whitney Kropp, Games Makers And My L...
Sunday Spotlight: Book Review of Pushing The Limit...
Tips For NaNoWriMo First-Timers
Friday Feature: Interview with Josin L. McQuein
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Can A Spoiler Destroy A Story?
Sunday Spotlight: Hollow Pike by James Dawson
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Scott Cramer's Tips For Self-Published Authors
Monday Musings: Sir Peter Stothard and Self-Publis...
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SECONDS OPENING FRIENDLY AT TAUNTON VALE IS WASHED OUT
Worcestershire Seconds have suffered the wash-out of their opening friendly game which formed part of their preparations for the 2019 campaign.
They had been due to visit Somerset from next Monday to play a three-day encounter at Taunton Vale.
But that match has been called off due to the ground being flooded.
The Seconds will now hope to start their warm-up programme against Shropshire in a one-day match at Wrekin College on April 7.
That fixture is set to be followed two days later (April 9) by the now traditional early season game against Worcestershire Academy at Kidderminster.
The Seconds competitive programme will get underway with an away Trophy encounter with Warwickshire on April 18.
The first home game in the 50 over competition will be against Leicestershire at RGS Worcester five days later.
The Championship campaign will start away to Lancashire at the end of April with the first home match in the three-day competition being staged at Barnt Green versus local rivals Warwickshire.
The Bears will also provide the Seconds with their first action in the T20 tournament at Stourport on June 6.
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Pakistan roller-coaster on the up
Posted by Q at Sunday, September 17, 2017 Pitched (15)
Life as a Pakistan cricket supporter is like being on a roller-coaster with similar emotions suffered by fans of the proverbial ‘yo-yo’ football teams that enjoy the highs of promotion before tumbling down again the next season.
The summer’s triumph in the ICC Champions Trophy was clearly a high and one that not many people saw coming.
But a glance at history shows that the Asians have never really been a consistent side and it really should have surprised nobody that they were able to fly under the radar to pull off such a stunning tournament success.
Whether they can carry it into the 2019 World Cup only time will tell and it is unlikely they will be among the favorites.
The 1992 World Cup triumph under the leadership of the legendary Imran Khan remains the nation’s pinnacle in the sport and a success that was borne out of adversity, with the side barely making it out of the group stage.
To quote the great man himself they fought like ‘cornered tigers’ and it was a never-say-die attitude that saw them all the way to the final and past an England team tipped for glory.
The current crop of players may not quite have the talent of their compatriots from 25 years ago but they have no less fighting spirit and were simply too strong for England in the semi-finals before taking apart rivals India in the final.
Pakistan have always been tough to beat once they get on a roll but they have also shown a brittle side in recent years with some poor defeats and displays.
Form in the months leading into the Champions Trophy was patchy, with a 4-1 ODI series loss to Australia but they did manage to beat a relatively weak West Indies side 2-1 in April.
Test results have not been much to write home about with losses to Australia and New Zealand in the past 12 months but, once again, they were too good for the men from the Caribbean.
Misbah-ul-Haq must take a lot of credit for the way he led the side from the turbulent times after the 2010 England tour, and his retirement will leave a huge void in the side both in leadership and batting.
Any success that Pakistan had in the five-day game was in no small way down to the veteran, who scored runs for fun after being handed the captain’s armband.
His 26 Test victories is a Pakistan record and the new man at the helm, Sarfraz Ahmed, has big shoes to fill in all three formats of the game.
All Pakistan’s recent success has been achieved without having a home to call their own with matches played in the United Arab Emirates, and it was a welcome sight to see international cricket back in the country.
The World XI may not be the strongest side that will ever visit Lahore but it is one of the most significant for a nation starved of matches on home soil since 2009, and the hope is that it will be the forerunner of Test cricket returning to Pakistan soil in the near future.
There will doubtless be many ups and downs for the Pakistan side in the future but, when they come, the peaks are certainly worth the wait.
Labels: CT2017, ICC champions trophy, Imran Khan, Misbah, Pakistan cricket, Pakistan vs World XI 2017, Q, Sarfraz Ahmed, World XI
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6 Underground Trailer: Ryan Reynolds and Michael Bay Blow Stuff Up
Michael Bay and Netflix just seem like a match made it heaven. Netflix has endless amounts of money to throw at filmmakers, and Michael Bay is a guy who knows how to spend money. Good, bad, or indifferent, you can never say Michael Bay’s movies don’t look like they cost a fortune. And his new one 6 Underground looks expensive as hell. Globetrotting adventure, with Ryan Reynolds, and giant magnets don’t come cheap. Plus, when you make a movie for Netflix, it’s free for subscribers. As long as it has three amazing stunts and doesn’t completely insult your intelligence, it’s fine! That’s a bar Michael Bay and Ryan Reynolds can clear.
Reynolds teams with Bay for the film, which is also written by Reynolds’ old Deadpool screenwriters Paul Wernick and Rhett Reese. Reynolds revealed the first trailer for the film on his Twitter account today. Here it is:
And here’s the film’s official synopsis:
6 Underground introduces a new kind of action hero. Six individuals from all around the globe, each the very best at what they do, have been chosen not only for their skill, but for a unique desire to delete their pasts to change the future. The team is brought together by an enigmatic leader (Ryan Reynolds), whose sole mission in life is to ensure that, while he and his fellow operatives will never be remembered, their actions damn sure will.
6 Underground debuts on Netflix on December 6.
Source: 6 Underground Trailer: Ryan Reynolds and Michael Bay Blow Stuff Up
Filed Under: netflix, ryan reynolds
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In a world without anonymity or crime, a detective meets a woman who threatens their security.
Genre: Movies, Sci Fi, Thriller
Actors: Clive Owen, Amanda Seyfried, Colm Feore
Director: Andrew Niccol
A pilot battles to save his family and the planet after an experiment for unlimited energy goes wrong.
Country: United States, Euro
Actors: Don Alphonso, Chloe-May Cuthill, Tygo Gernandt
Harriet is a retired businesswoman who tries to control everything around her. When she decides to write her own obituary, a young journalist takes up the task of finding out the truth resulting in a life-altering friendship.
Actors: Shirley MacLaine, Amanda Seyfried, AnnJewel Lee Dixon
F*&% the Prom
Maddy and Cole were inseparable friends until high school started and Maddy became the most popular girl on campus. When she starts feeling lonely and heartbroken, she reconnects with Cole and the duo conspire to destroy the ultimate teen popularity contest - the Prom.
Actors: Danielle Campbell, Joel Courtney, Madelaine Petsch
The Assassins Code
A rookie detective, son of a dead disgraced cop, works to solve his first major case while under the watchful eye of a ghost-like assassin.
Actors: Justin Chatwin, Peter Stormare, Mark Thompson
A woman (Jacobson) learns her brother (Franco) has relapsed on heroin.
Actors: Dave Franco, Tim Matheson, Jane Kaczmarek
A young autistic woman runs away from her caregiver in an attempt to submit her manuscript to a "Star Trek" writing competition.
Actors: Dakota Fanning, Toni Collette, Alice Eve
Outside a mountain town grappling with a series of abductions and murders, Paul (Antonio Banderas), a reclusive writer, struggles to start what he hopes will be a career-saving screenplay. After a tense encounter at a diner with a drifter named Jack (Jonathan Rhys Meyers), Paul offers Jack a place to stay-and soon the edgy, demanding Jack muscles his way into Paul's work and the two men begin a jagged game of one-upmanship that will bring at least one tale to an end.
Actors: Antonio Banderas, Jonathan Rhys Meyers, Piper Perabo
In the near future, when communications go offline at a remote nuclear power plant isolated in the desert, a young safety inspector, Abby Dixon, is forced to fly out to bring them back online. Once inside the facility, mysterious clues and strange behaviors cause Abby to have doubts about the sanity, and perhaps identities, of the two employees onsite.
Actors: Tom Sizemore, Sarah Habel, Dominic Monaghan
Trailer: Anon
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Book Review Index by Author
The Book Fairies
The Introvert Confounds Innocence - Michael Paul Michaud
THE INTROVERT CONFOUNDS INNOCENCE continues the story of the eponymous anti-hero introduced in THE INTROVERT.
With his life disrupted by an unscrupulous work colleague and a bully at his son Toby’s school, things go from bad to worse when his neighbor’s abusive boyfriend goes missing, plunging the introvert into the center of a murder investigation.
Increasingly hounded by a meddlesome detective, and with his thoughts continually urging him to make people “red and open” and to “achieve it” with his girlfriend Donna, what follows is a sometimes brutal, oftentimes hilarious, and absurdist account of the life of one very anti-social and unexpected anti-hero.
What did I think?
When reading The Introvert one rainy Saturday afternoon, I really didn't want it to end and my wish was granted with The Introvert Confounds Innocence being next in my reading queue - hurrah! You could read this book as a standalone but I think it definitely works better as a series, after all, the introvert himself is a serial killer. He's not your traditional serial killer by any means; he doesn't go out looking for people to kill, it's more like they present themselves to him as people who deserve to become 'red and open'. As a literal thinking killer with feelings, I think of our nameless anti-hero as a cross between Sheldon Cooper from The Big Bang Theory and Dexter Morgan from Dexter.
I love the simple but clever covers of these books and The Introvert Confounds Innocence shows a new addition to our anti-hero's life. I think his partner, Donna, not standing along with the family says a great deal about how anti-social our anti-hero really is. Does he actually love her or is she simply a means to his 'achieving it'?
There is a lot going on in the 226 pages of this book: the introvert's son is being bullied, he has a new competitive colleague at work and his next door neighbour is the victim of domestic abuse. With many contenders for the next person to become 'red and open', I couldn't read fast enough to see how this story would play out. Some of the interactions with his new colleague at work had me guiltily laughing out loud as our introvert smashes several of the equality and diversity protected characteristics to smithereens in one fell swoop. You really can't be offended by it as he doesn't mean it in a derogatory way, he is just being literal and there's nothing wrong with that when that's the way you are made.
Although not a criticism by any means, there was only one thing I personally didn't like in the book and that was the way the weird English detective spoke, however, the repetitive, often lyrical nature of prose did fit well with the book. He just annoyed the hell out of me as it felt like he was talking to a dog most of the time but I think that was part of his character as he came across as a bumbling friendly guy but he was like a bloodhound that has the scent of blood.
Leading on very nicely indeed to Book 3: The Introvert Bears Filthy Witness, The Introvert Confounds Innocence is a wonderfully quirky instalment in this awesome series. I can't wait to see what happens next to the introvert and I have to confess that I am most definitely addicted to this highly original series; so just try and stop me reading the books again while I wait (im)patiently for Book 3.
I chose to read an ARC and this is my honest and unbiased opinion.
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Posted by Michelle Ryles at 11:21 No comments:
Labels: co-workers, dog, dog lover, family, introvert, love, murder, relationship, relationships, serial killer, work
The Introvert - Michael Paul Michaud
A vacuum salesman by day, the introvert lives a quiet life alone with his dog until a work relationship and a dark secret from his past team up to create an uncomfortable imbalance in his otherwise ordered life, one that soon finds him squarely at the center of a murder investigation. With his thoughts continually urging him to make people “red and open” and to “achieve it” with his girlfriend Donna, what follows is a sometimes brutal, oftentimes hilarious, and absurdist account of the life of one very anti-social and unexpected anti-hero.
What a totally awesome book! I love something a bit different and boy, was this different! As a self-confessed introvert, I was attracted to this book by its simple cover as I've never been afraid to stand apart from the crowd, in fact I much prefer it! Thankfully, I don't share any of the dark traits of our nameless anti-hero but, rather like my favourite serial killer, Dexter, he only makes people 'red and open' who deserve it.
I knew from the start that I was going to enjoy this book as the introvert comes up against bureaucratic red tape when he attempts to renew his drivers licence. After queuing for 40 minutes he leaves empty handed but with dark thoughts of stabbing the clerk with her own letter-opener. Don't get me wrong, this isn't a horror story; it's definitely more of a black comedy as I found myself giggling at the situations the introvert finds himself in, especially when he attracts the attention of his colleague, Donna. He finds that although he can 'achieve it' on his own, it's much better when Donna helps him.
I suppose seeing the more human side of him as his relationship with Donna progresses made it easier to take his side when things go spectacularly wrong. I actually found him a little naïve with almost a childlike innocence when the reasons behind his actions become apparent. He does have a good heart but he can't control his impulses for making people who deserve it 'red and open'.
As a very literal person, which my family and colleagues will attest to, I found it quite hilarious to see how the introvert interprets things. I don't think I'm quite as bad as him but there are some scenes with a police officer and police inspector that had me both sniggering at the audacity and silently applauding the literal brain of our anti-hero.
With an anti-hero you can't help rooting for and an intriguing storyline of a strange life and a murder investigation, The Introvert is impossible to put down once you pick it up. At only 160 pages long, it's so easy to read this original and quirky book in one sitting, which is what I did, but I really didn't want the story to end. Thankfully, it doesn't end there with Book 2: The Introvert Confounds Innocence already published and Book 3: The Introvert Bears Filthy Witness in the pipeline.
The Introvert may very well be my new guilty pleasure and it's definitely a book I'd read again as I'm sure I have missed some of the nuances of this wonderful and darkly charming anti-hero. It's the perfect book to pick up if you're at a loose end on a rainy Saturday afternoon. Highly recommended for fans of Dexter and black comedy.
Labels: co-workers, dog, dog lover, introvert, love, murder, relationship, relationships, serial killer, work
BLOG BLITZ: Dying To Tell - Keri Beevis
As the only survivor of a horrific car crash, Lila Amberson believes she is on the road to recovery after she is released from the hospital. Her memories of the accident are blurred though and a series of unsettling incidents leave her fearing for her safety. Does she have survivor's guilt or is something more sinister at play?
Jack Foley is reeling from the shock of losing his sister in the crash and when he first meets Lila, he lashes out, blaming her for Stephanie's death. But when Lila gives him a locket that she believes belonged to his sister, it presents more questions than answers.
As Lila and Jack work together to find out what really happened on the night of the accident, they are unaware that someone is watching them closely. Someone who has much to lose if the truth comes out, and someone who is prepared to do everything necessary to ensure all loose ends are taken care of.
Woah! My creep-o-meter went into total overdrive whilst reading Dying To Tell by Keri Beevis. There are one or two characters who literally made my skin crawl and it's not that they were particularly unpleasant, but rather that they seemed to have a touch of menace and deeply buried secrets about them. To get this feeling from an author's writing is one of the magical things I love about reading! Keri Beevis has written a number of books but this is the first one I have read; it definitely won't be my last!
Lila is a brilliant character with an intriguing story. We've all been on bad dates but Lila's must be the worst when she is involved in a fatal two car collision. Lila can't remember exactly what happened in the crash but she is drawn to the funeral of the driver of the other car, Stephanie. Sparks fly when she meets Stephanie's half-brother, Jack; sparks of anger at first but most definitely sparks of electricity as the pair are helplessly attracted to each other. I loved this part of the story as Lila is very vulnerable and opens her heart to Jack but suffers the same insecurities as we all do in a new relationship.
There's definitely more to the crash than meets the eye and I thought I had it all worked out but I was only a teeny tiny bit right. Bravo Keri Beevis! I gave Keri a virtual standing ovation when I was proved mostly-wrong and my eyes raced ahead of my brain in an attempt to devour every word on the page at record speed.
Reading Dying To Tell has definitely piqued my interest in other books written by Keri Beevis. Whereas Dying To Tell is set in Norwich, her previous books are set in America but judging by the 5 star reviews they are just as brilliant. Keri Beevis is a new author to add to my favourites list and Dying To Tell is a book I'll be raving about for quite some time.
Keri Beevis wrote her first novel at age twenty, but it was a further twenty years before she was published after entering the Rethink Press New Novels Competition 2012. Her entry, Dead Letter Day, was a winner, earning her a publishing contract, and the book proved to be a minor hit, leading to a sequel, Dead Write. However it was Keri's third novel, standalone mystery thriller The Darkness Beneath that gained her the most success, along with many new fans, both in the UK and the USA.
Born in the village of Old Catton, less than a mile from where Anna Sewell was living when she wrote Black Beauty, Keri had a passion for reading and writing from a young age, though her tastes veered more to the macabre.
Today she still lives in Norwich, along with her two naughty kitties, Ellie and Lola, and a plentiful supply of red wine (her writing fuel), where she writes a comedic lifestyle column for a local magazine. She loves Hitchcock movies, exploring creepy places, and gets extremely competitive in local pub quizzes. She is also a self-confessed klutz.
Keri’s previous books have all been US based and she is looking forward to the release of her first UK based novel, which is set in her beautiful home county of Norfolk.
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Labels: accident, car accident, car crash, crash, family, family secrets, Norwich, psychological, relationship, relationships, secrets, thriller
The Guardian of Lies - Kate Furnivall
1953, the South of France. The fragile peace between the West and Soviet Russia hangs on a knife edge. And one family has been torn apart by secrets and conflicting allegiances.
Eloïse Caussade is a courageous young Frenchwoman, raised on a bull farm near Arles in the Camargue. She idolises her older brother, André, and when he leaves to become an Intelligence Officer working for the CIA in Paris to help protect France, she soon follows him. Having exchanged the strict confines of her father's farm for a life of freedom in Paris, her world comes alive.
But everything changes when André is injured - a direct result of Eloise's actions. Unable to work, André returns to his father’s farm, but Eloïse’s sense of guilt and responsibility for his injuries sets her on the trail of the person who attempted to kill him.
Eloïse finds her hometown in a state of unrest and conflict. Those who are angry at the construction of the American airbase nearby, with its lethal nuclear armaments, confront those who support it, and anger flares into violence, stirred up by Soviet agents. Throughout all this unrest, Eloïse is still relentlessly hunting down the man who betrayed her brother and his country, and she is learning to look at those she loves and at herself with different eyes. She no longer knows who she can trust. Who is working for Soviet Intelligence and who is not? And what side do her own family lie on?
I discovered Kate Furnivall through TBC on Facebook so joining that group is the best thing I ever did as I absolutely adore her books. As a keen reader of historical fiction, I know how difficult it can be to bring an era to life but Kate Furnivall does this impeccably. What an amazing talent to be able to transport the reader to miscellaneous locations and time periods; whether it's early 20th Century Egypt in Shadows on the Nile, war torn Italy in The Liberation or post-war France in The Guardian of Lies I feel as if I'm travelling the world through Kate Furnivall's wonderful books.
In The Guardian of Lies we launch straight into the action with Eloïse acting as a getaway driver for her brother André. With a car chase that would rival James Bond, I had my heart in my mouth and was left breathless as the action unfolds. The pacing doesn't give up there, even when Eloïse and André return to their father's farm in Arles; in fact it felt more dangerous in the idyllic countryside of The Camargue with civil unrest over an American airbase being built on their farmland. With such a great opportunity to spy on the American airforce, Eloïse can't tell which side her family, friends and neighbours are on. The question on my lips throughout the whole book was: who can she trust?
Oh my word, this is another outstanding novel by Kate Furnivall. I almost managed to read it in one sitting, if only I didn't have to eat and sleep! I really couldn't put it down and it's unusual for this to happen to me when reading historical fiction as sometimes it's quite fact-heavy and dry so I need to take regular breaks. Kate Furnivall's writing is so multi-faceted that it awakens the senses as you see, hear and smell every sight, sound and action along with the characters.
I was a little concerned that the story might be confusing, as is often the case with Russian espionage, but I needn't have worried as the story is easy to follow and we aren't overrun with characters. This proves yet again that Kate Furnivall is an exceptional storyteller. I think of Kate Furnivall is a literary knitter; she spins such a good yarn.
The Guardian of Lies is an exceptional novel by one of the finest historical fiction authors I've ever come across; so grab your passport and pick up a copy to be transported to post-war France from the comfort of your armchair. A highly recommended read and one I shall definitely be recommending for a long time to come.
Labels: espionage. spies. spy, family, farm, France, lies, Russia, Russian spy, Russians, secrets, thriller
BLOG BLITZ: Cold Echo - CJ Carver
Should you trust your best friend with your life?
When they were children, Harry, Lucas and Guy were best friends. But then they made a mistake that shattered their friendship and forced them to cut all ties.
Years later a man’s head is discovered in the woods, skinned and with the tongue cut out. The police call on Harry, a psychotherapist, to help with the case, and when it transpires the victim is his old friend Guy, old skeletons begin to surface.
Then one of Harry’s clients goes missing.
Forced into a desperate hunt to save the boy, Harry finds himself closing in in on a terrible secret, a secret someone will do anything to keep buried…
This is my second CJ Carver book and although it didn't quite knock Over Your Shoulder off the top spot, it was still an excellent read. CJ Carver writes a might fine thriller with so many strands woven through the story, giving it a multi-layered effect. The pacing is fast and the pages turn effortlessly as the story unravels.
I love books with secrets in them and Cold Echo starts with Harry, Guy and Lucas as young boys sharing a secret that will haunt them all their lives, with some lives proving to be shorter than others. The intrigue was certainly ramped up to full when, many years later, a head is found that belongs to Guy. As if that wasn't intriguing enough, Harry is a psychotherapist who is called in to help the police in this case, a case that sees one of his clients go missing and brings him back into contact with Lucas and another face from their past.
Cold Echo is rather like a supermarket trolley; it goes in unexpected directions. Although I didn't fully engage with the characters, I was completely riveted by the story and found it very hard to put down as there are so many strands of intrigue to unravel, it's like a ball of wool that has been in the paws of a kitten. I really enjoy CJ Carver's writing; it's so intriguing, gripping and filled with eye-opening surprises.
Winner of the CWA Debut Dagger for her first novel Blood Junction, CJ Carver has written a further ten critically acclaimed novels. Spare Me The Truth, the first in the Dan Forrester series, was shortlisted for the Ngaio Marsh Award 2017.
Half-English, half-Kiwi, CJ lived in Australia for 10 years before taking up long-distance rallies, driving London to Saigon, London to Cape Town and covering 14,000 miles on the Inca Trail in South America.
CJ began her writing career by writing about her adventures, eventually becoming a travel writer for various national publications including The Telegraph, The Independent, The Guardian, Autocar. She is co-founder for the Women’s World Car of the Year Award.
CJ has been a judge for the Thriller Awards in the USA. Her books have been published in the UK, USA and translated into several languages. She lives just outside Bath.
Labels: friends, friendship, psychotherapist, psychotherapy, schoolfriends, secrets, thriller, vulnerable children, youngsters
Morecambe & Vice Blog tour: Blanket of Blood - Eileen Wharton
Morecambe & Vice, the North-West's crime-writing festival, is in its third year and this year Books on the Bright Side Publicity have organised an epic blog tour to showcase all of the brilliant authors taking part. I am delighted to be partnered with Eileen Wharton, a fellow North-Easterner, and I am releasing my review of Blanket of Blood as part of the tour.
Find out more about the festival and buy tickets from https://www.morecambecrimefest.co.uk/
The body of a baby is found in the woods but all is not as it seems.
A twisted serial killer is targeting pregnant teenage girls.
DI Blood races against the clock to stop the most chilling murderer he’s ever hunted. His private life meanwhile threatens to distract him and derail his investigation.
Any mistake, any hesitation on his side, could cost another innocent life...
I have been raving about Eileen Wharton since reading her extremely funny book, The M Word, last year; I love Eileen's sense of humour and if you ever get the chance to go to an author event where she's appearing (Morecambe & Vice, perhaps?) you don't want to miss it. I put on my serious head as I picked up her pre-The M Word book, Blanket of Blood, but really should have known that there would be some tea-spluttering laugh out loud moments in a thriller written by Eileen Wharton.
The prologue is pretty chilling as a young girl is abducted as she contemplates buying something literally 'off the back of lorry'. I was plunged deeper into darkness in chapter one with the discovery of a baby's body in the woods and the introduction to DI Gary Blood. I went from goosebumpy chills of the crime to choking laughter at Blood's circumstances on waking. There it is! Eileen Wharton's trademark humour; you just can't keep it down and I love it.
What makes this book different from run-of-the-mill thrillers is, not just the humour, but the depth of character Eileen Wharton has created in Gary Blood. DI Blood is one thing but family man Gary Blood is a whole different beast when emotions are added to the mix. Gary has his own demons with his health, an ex-wife who doesn't want to leave, inappropriate feelings for his sister-in-law and his struggle to accept the lifestyle of his daughter. With so much going on in his life, along with a stressful job, I'm surprised he wasn't found preparing to jump off the Tyne Bridge!
The story about the abduction of pregnant girls is chilly, scary and very clever as we get to see inside the mind of a killer and the scars that have been left there. It's sobering to be reminded how our actions can affect others, especially impressionable children. I'm not condoning the crime, but by showing the reader the reason behind it is very refreshing and clever of Eileen Wharton as it is rare to see the full picture in a book.
Blanket of Blood is superbly written with a cunning criminal, a seriously flawed detective, a dark, original murder method and lashings of dry humour to keep the reader grounded. It's fast-paced, gripping, unique, amusing and very very highly recommended; I can guarantee that you won't have read anything like this before. I do hope to see the return of DI Blood in the future.
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Posted by Michelle Ryles at 00:20 1 comment:
Labels: family, murder, North East England, police, police investigation, police procedural, thriller
BLOG TOUR: Lake Child - Isabel Ashdown
You trust your family. They love you. Don't they?
When 17-year-old Eva Olsen awakes after a horrific accident that has left her bedbound, her parents are right by her side. Devoted, they watch over her night and day in the attic room of their family home in the forests of Norway.
But the accident has left Eva without her most recent memories, and not everything is as it seems. As secrets from the night of the accident begin to surface, Eva realises - she has to escape her parents' house and discover the truth. But what if someone doesn't want her to find it?
An edge-of-your-seat, atmospheric psychological thriller for fans of Lucy Clarke and Erin Kelly.
What an outstanding book! Atmospheric doesn't even begin to describe it; Isabel Ashdown perfectly conjured the landscape in Norway, so much so that I felt as if I should have been wearing snow boots and a padded jacket whilst reading Lake Child.
Eva's whole story is massively intriguing from the start; she's recovering from a mysterious accident and her parents have her locked in the attic. I couldn't read fast enough to find out why she was locked in the attic and to discover the mystery surrounding the night she was involved in a crash. Then just as the story reaches fever pitch, we are distracted by the interview of a grandmother of a missing baby in England that threw my mind into turmoil and made me put on my virtual running shoes to see how the two stories were linked. I thought I saw it coming but, with an abundance of family secrets stashed in the closet, I could only see the tip of the iceberg.
Isabel Ashdown must be part-Viking to have embraced the scandi-noir genre so expertly. I say scandi-noir but maybe this is scandi-psych as it twisted my brain into knots with the shots of intrigue and surprise being fired at me relentlessly. As chilly as the landscape is, the warmth of family and friendship shines through, excluding the dysfunctional family in England of course; they wouldn't have looked out of place on the Jeremy Kyle show, that's for sure. The contrast between the two families is portrayed excellently; they really are like chalk and cheese.
Gripping from the start, Lake Child is filled with mystery, intrigue and dark family secrets. Set against the backdrop of a cold and beautiful Norwegian landscape, it's a real ice-gripper. A highly recommended read.
Labels: Abduction, Dysfunctional family, family, family secrets, missing, missing children, Norway, psychological, scandi, Scandinavian
BLOG TOUR: The Ten Thousand Doors of January - Alix E. Harrow
EVERY STORY OPENS A DOOR
In a sprawling mansion filled with exotic treasures, January Scaller is a curiosity herself. As the ward of the wealthy Mr. Locke, she feels little different from the artefacts that decorate the halls: carefully maintained, largely ignored, and utterly out of place.
But her quiet existence is shattered when she stumbles across a strange book. A book that carries the scent of other worlds and tells a tale of secret doors and danger, of love and adventure. With each page she reads, January learns impossible truths about the world and discovers a story increasingly entwined with her own,
Open a door to another world and discover the most spellbinding debut of 2019, perfect for readers of THE NIGHT CIRCUS, THE THIRTEENTH TALE and THE BINDING
The Ten Thousand Doors of January has to have one of the most striking covers I have ever seen; the door handle and keys give it a definite hint of Wonderland, so I prepared myself to expect the unexpected. The pacing is quite slow to start with so I wasn't grasped immediately by the story but soon found that January Scaller had slowly burrowed under my skin as I joined her on her fascinating journey.
This is like a book within a book as January reads from a book she finds; I do wish she could have found this book in chapter one though, as chapter one of 'The Ten Thousand Doors' is included in chapter two of the book, chapter two in chapter three and so on and so forth. I have a bit of OCD about numbers so I did struggle with this at first but this minor annoyance was quickly forgotten as I became immersed in the story.
Alix E. Harrow clearly loves letters and words as much as I love numbers. She has such an affinity for seeing the magical in the mundane; who would have noticed the letter 'H' in the word 'House' as being like a roof with two chimneys? There are sublime descriptions of other letters, that I'll not mention for fear of spoiling for others, that made me want to give a standing ovation to Alix E. Harrow. As a numbers gal, I would never have seen such beauty in letters without her guidance.
I feel completely honoured to have accompanied January on her journey as she discovers her past and her ability to open magical doors into other worlds. Isn't that what we readers do every time we open a book? I didn't realise how affected I was by her story until near to the end when I found myself swallowing a lump in my throat.
For readers who loved falling down the rabbit hole with Alice, follow January through her magical doors and discover worlds built of words. This magical, imaginative and captivating debut is like a love letter to the English language; Alix E. Harrow has opened my eyes to the magic in every word and I will never look at letters in the same way again.
Labels: book, books, daughter, family, family history, fantasy, father, history, magic
BLOG TOUR: Endgame (Detective William Fawkes #3) - Daniel Cole
A locked room. A dead body. A secret that went to the grave.
When retired police officer Finlay Shaw is found dead in a locked room, everyone thinks it's suicide. But disgraced detective William 'Wolf' Fawkes isn't so sure.
Together with his former partner Detective Emily Baxter and private detective Edmunds, Wolf's team begin to dig into Shaw's early days on the beat. Was Shaw as innocent as he seemed? Or is there more to his past than he'd ever let on?
But not everyone wants Wolf back - and as his investigation draws him ever deeper into police corruption, it will not only be his career on the line - but the lives of those he holds closest as well...
Oh I can't even begin to tell you how much I've been looking forward to this book and I'm delighted to say that it did not disappoint. Endgame is the third in the Detective William Fawkes (Wolf) series, following on from Ragdoll and Hangman. I don't know how Daniel Cole does it but each book seems do outdo the previous one, despite them all being brilliant in their own right.
Endgame grips the reader by the throat right from the start with a double whammy: an apparent suicide and the arrest of Wolf. Wolf is convinced his old mentor, Finlay, wouldn't have killed himself and he does a deal with the police commissioner, who happens to be Finlay's old friend Christian, to allow him to investigate what everyone thinks is an open and shut case. Bringing the gang back together, Wolf teams up with old pals Baxter and Edmunds and what a trio they make. The sexual tension between Wolf and Baxter is palpable, reminiscent of Ross and Rachel in a will they/won't they scenario. To complete the Friends analogy, I really like Edmunds who is a bit of a Monica in his dogged determination and organisation skills.
As Wolf investigates Finlay's death, he takes a closer look at Finlay's life. Roll back to 1979 with Finlay and Christian hailed as heroes in a drugs bust, but not everything is as it seems. Buried secrets don't stay buried for long, especially not when Wolf is on the case. It's like a game of chess and just when one player thinks they are about to call checkmate, the game is turned on its head. I loved all these twists and turns that kept my heart racing in my chest and my eyes racing down the page.
I think you could possibly read Endgame as a standalone but I really would recommend you read Ragdoll and Hangman first as it does have links to the previous books; so anyone picking up Endgame as their first Daniel Cole book will undoubtedly want to read the previous two books right away to see the full picture. The whole series is amazing, but Endgame is the cherry on top.
Daniel Cole writes so vividly and energetically that his words seem to fizzle and crackle on the page; it's so visual that I really wouldn't be surprised to see this series on tv in the future. Endgame is a blistering conclusion to the Ragdoll trilogy but I'm hoping it's not the last we've seen of Wolf and Baxter. As gripping as a vice, Endgame is an electrifying heart-in-your-mouth thriller; it has more thrills and stomach clenching moments than a rollercoaster and a waltzer merged together. Absolutely superb and definitely unmissable!
Labels: detective, killer, murder, police, police investigation, thriller
BLOG BLITZ: Bloodline - Pamela Murray
When a young boy discovers a man’s body lying in a doorway, DI Burton and DS Fielding are called to the scene.
Believing the man was homeless, the police are shocked to discover the true identity of the victim; a Detective Constable from London who was working undercover.
But when the DNA from the victim is linked to a cold case Burton and Fielding find themselves looking into another unsolved murder.
And as the case unfolds, the detectives are faced with unpicking through a web of lies and deceit. But can they solve the murders before any more blood is spilt?
I came across Pamela Murray as she is a local North East author and although I haven't yet read her debut, Murderland, I was eager to read the second book in the Burton and Fielding series, Bloodline. So it is without any doubt that I can say that Bloodline can be read as a standalone as I found it gripping, intriguing and a mighty-fine page turner. It has definitely made me want to read Murderland as soon as possible to get to know Burton and Fielding a little better; there's definitely a lot more to come from this pair.
The prologue is an amazing double ended hook, set in 1986 with a murder and present day with a man spying on his girlfriend as she meets with another man. How these stories weave together and become clear later on is simply brilliant, but these threads are left tantalisingly dangling when the body of an undercover cop is discovered. Then there's a double whammy of tasty storyline as the undercover case is picked up and the victim's DNA brings up a match in the database linking him to a cold case.
I loved the DNA storyline, both the links to the victims and the DNA kits that you see for sale these days. I must admit, I am slightly sceptical as to what their purpose is as it seems an easy (and sneaky) way to collect and record DNA of unsuspecting people rather than just give them clues as to their ancestry. I didn't realise that the DNA kits also match your results with others who have taken the test, although they do warn people in advance that they can discover illegitimacy, adoption or donor-conception. It may seem like a bit of fun buying such a gift for the person who has everything but imagine the repercussions if they found out that their whole life was a lie. I love books that have thought-provoking discussion points like this, so I have found myself thinking about this long after finishing Bloodline.
With strands of intrigue woven through the storyline like a double helix, Bloodline is a fast-paced gritty and compelling thriller. You can't fail to be hooked by the amazing prologue and it's impossible to put the book down after that. A highly recommended read from an outstanding local talent.
Pamela Murray is from the North East of England, and has spent most of her life living in Boldon. She began writing at an early age when she and her school friend used to write stories for one another. The writing continued on and off over the years, but was only recently reignited when the same school friend introduced her to the local writers group she was in.
Pamela had intended to enter Journalism after leaving school but found herself going to work in a Public Library instead, and has always had more than a passing interest in books and literature.
When not writing, Pamela is passionate about Cinema and her three grandchildren. She has also appeared as a Supporting Artiste in two episodes of the hit TV crime series "Vera".
Labels: DNA, family, family secrets, family tree, lies, Manchester, murder, police, police investigation, police procedural, undercover
BLOG TOUR: A Shadow on the Lens - Sam Hurcom
The Postmaster looked over my shoulder. As I turned to look I saw a flicker of movement from across the street. I felt unseen eyes peer at me.
He walked away without another word. I watched as he climbed onto his bicycle and sped away down the street. I turned back and looked over my shoulder.
Someone had been watching us.
1904. Thomas Bexley, one of the first forensic photographers, is called to the sleepy and remote Welsh village of Dinas Powys, several miles down the coast from the thriving port of Cardiff. A young girl by the name of Betsan Tilny has been found murdered in the woodland - her body bound and horribly burnt. But the crime scene appears to have been staged, and worse still: the locals are reluctant to help.
As the strange case unfolds, Thomas senses a growing presence watching him, and try as he may, the villagers seem intent on keeping their secret. Then one night, in the grip of a fever, he develops the photographic plates from the crime scene in a makeshift darkroom in the cellar of his lodgings. There, he finds a face dimly visible in the photographs; a face hovering around the body of the dead girl - the face of Betsan Tilny.
I enjoy reading both historical fiction and crime thrillers so my interest was already piqued when I read the blurb of A Shadow on the Lens. Then when I read that the book is set in the small Welsh village of Dinas Powys, which is where my maternal great great great grandfather was born in 1827, I just had to read it. My ancestor had moved to the North East by 1904 (which is when this story is set), maybe leaving brothers and sisters in Dinas Powys, so I was very excited to read a book set in the village he left behind; although no Norris's featured in the story.
It took me a little while to get into the rhythm of the book but the murder of Betsan Tilny is so very intriguing that it keeps the pages turning nicely. A forensic photographer is summoned to the village to investigate the crime and this was the first oddity to intrigue me - why a photographer and not a police inspector? It soon becomes clear that the locals want Thomas Bexley to simply take his photos and leave their village without discovering who or what has committed the crime. Everyone in the village appears to be hiding something so the sooner Thomas is gone the better.
We take it for granted these days that we take a photo and see it instantly but there's something so very mystical and magical about developing photographs and back in 1904 (only a few years after the Kodak Brownie was introduced) photos were developed on plates in a dark room. When Thomas develops his photographs he can't believe his eyes as the murder victim appears as a ghostly apparition. When Thomas is suddenly struck down with a fever and his negatives disappear, he wonders if he imagined it all but he remembers clues from the photographs that he couldn't possibly have known about beforehand. This puts him in more danger than he could ever have imagined.
I loved the spooky supernatural element to the story which really makes A Shadow on the Lens something different. Encompassing so many genres means that it will appeal to crime, historical and fantasy readers, which is not something that many books can claim to do. A Shadow on the Lens is a spooky, goosebumpy, gothic-style historical crime thriller and a fantastic debut from Sam Hurcom.
Sam Hurcom was born in Dinas Powys, South Wales in 1991. He studied Philosophy at Cardiff University, attaining both an undergraduate and master's degree. He has since had several short stories published and has written and illustrated a number of children's books. Sam currently lives in the village he was raised in, close to the woodlands that have always inspired his writing.
A SHADOW ON THE LENS is Sam's debut novel.
Labels: forensics, ghost, gothic, murder, mystery, photographer, police, police investigation, thriller, Wales
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Internal/External Molds, Casts clarification
By Rocky Stoner, August 1, 2017 in Questions & Answers
Rocky Stoner 64
Location: Eastern WV, USA
Please clarify for local discussion.
Referencing the attached sketch:
First is a coin simulating a fossil. If split at the red line, there would be 2 pieces of external mold. Correct ? or incorrect ?
Second is a lens shape, like a saucer or moult of a pygidium. If split at the red line, there would be 2 pieces of external mold. Correct ? or incorrect ?
Third is an egg or complete bivalve. If split at the red line, there would be 2 pieces of external mold and 1 internal mold. Correct ? or incorrect ?
All 3 assume that the specimens have dissolved an left a void which if filled would be the cast. Correct ? or incorrect ?
The local argument is that the pygidium moult example is 1 external mold (top) and 1 internal mold (bottom) because it is the "internal" side of the animal. I don't think that is correct.
Just a local discussion needing clarification, thanks.
http://www.ucmp.berkeley.edu/paleo/fossilsarchive/casmol.html
Fossildude19 10,771
Veteran Shale Splitter
Location: Connecticut, United States. Lower Jurassic, Shuttle Meadow & East Berlin FMs
This is a sticky wicket, that has been discussed here before.
More topics.
Question 1 - Correct
Question 3 - a - Correct. b. They are also called internal casts.
Question 4 - Correct.
Argument. - If there is integument, (exoskeleton material) it is a cast. IMO
If there is no integument, in my opinion, it would be a mold, because it is the bottom of the top mold, and the integument is the cast.
Others will chime in, I'm sure.
Thanks Tim, I'm with you, mostly.
Where you say:
From what I've read I would not call that an internal cast. What if it were half of a bivalve ... one shell ? Or what if it were a complete bivalve that was opened 90 degrees ... or 180 or 1 degree ? Would you then call it an internal cast ?
The only cast I see would be the integument.
I'm new, so please bear with me. Just want to be clear. Will check the link provided too.
As I tried to explain regarding the pygidium example, "The bottom half is the external mold of the internal surface of the pygidium, not and internal mold".
35 minutes ago, Rocky Stoner said:
Well, if you use metal working as an example -
You start with the mold.
You pour liquid heated metal into the mold.
You open the mold when cooled - and you have a cast, right?
So when the shell gets filled with mud, it hardens, shell dissolves away, you have a cast of the interior of the shell.
People call these, correctly or incorrectly, internal molds or internal casts. I see it as a cast, because it is free of the surrounding matrix, and is an item unto itself, like a pot that has been cast in iron.
If you plopped the cast into liquid latex, then removed the cast when the latex cools, you then have a mold of the cast.
You can go around and around with this ... not sure you will get any direct answers one way or the other, ... I have seen them described as internal molds and internal casts.
In the case of your argument, it could also be argued that the dissolved shell is much like the integument, therefore - the left over is a cast.
Whatever floats your boat, Rocky.
Oh yea, then we've got the Steinkern ....
As long as we get our point across, there appears to be no right or wrong.
Very interesting link,
2 minutes ago, Rocky Stoner said:
No problem, always happy to confuse the issue further.
Was clear as mud, now beginning to solidify.
Thanks Tim for covering all points of view and not referring to an opposing view as nonsensical!
BobWill 828
Location: Cooke County,Texas
This is one that we have never had total agreement on even though much time and effort has been applied to the subject. You will see a steinkern referred to as both an internal mold and an internal cast. For purposes of this forum and most web based "science" magazines it doesn't seem to matter unless it leaves you wondering which one is being referred to..
You will not however, see a steinkern referred to as an internal cast in a traditional peer review publication.
Usually the discussion in a peer reviewed journal about a fossil is separated from the illustrations and the reader needs to know what the fossil looks like when reading the text. Paleontologists always refer to a mold as the thing capable of reproducing a copy of the original. In the case of the internal surface of a gastropod, for example only an internal mold could be used to reproduce a copy of the original internal surface. Making that kind of copy is not something that is paleontologists usually do but it reflects the use of the words mold and cast the same way they are used by sculptors. In art you don't start with a mold, you start with an original. From that you make a "mold" and from that you make a "cast", a copy of the original. In the case of a fossil mold or cast the original is the shell that dissolves away as you said. A sculptor never makes a cast of the inside of anything and this is probably why there is so much confusion. If they did they would use an internal mold because it is always a mold that makes a cast of the original, whichever surface you are copying.
if you want to use the terms like a paleontologist it goes like this using the example of a clam because it will often show growth lines on the outside but not on the inside.:
A concave fossil showing growth lines is an external mold.
A convex fossil showing the growth lines in an external cast (copy of the original outer surface).
A convex fossil without growth lines (steinkern) is an internal mold ( could make a copy of the original internal surface).
A concave fossil without growth lines is an internal cast (a copy of the original internal surface which is itself concave).
In short, if it looks like either original surface it's a cast and if it could be used to reproduce either original surface it is always a mold just like the terms are used in sculpture. Anyone who disagrees should be able to show us an example of a steinkern being called an internal cast in a traditional peer reviewed journal and please this time not just a list of titles we may not have access to.
DPS Ammonite 2,393
October 2016 MOTM
Collections Curator
Location: Scottsdale, Arizona
I agree with almost everything that BobWill said. Nearly all professional paleontologists and geologists consider the material that infills a clam with both shells closed is an internal mold. What Bob said about clams is very useful and true as long as both shells are convex and not flat or concave on the outside:
"using the example of a clam because it will often show growth lines on the outside but not on the inside.:
A concave fossil without growth lines is an internal cast (a copy of the original internal surface which is itself concave)."
Here are several other reasons why the material inside of a clam should never be called an internal cast:
1) At what point does the internal cast of material inside of the clam become an external mold as the clams shells are fossilized in increasingly open positions: 10 degrees, 90 degrees or 180 degrees. All material deposited next to the shells should be called a mold regardless if the clam is completely closed or not. The shape of the intererior of the shell (concave, flat or convex) does not define whether or not a cast or mold can be produced.
2) An internal cast refers to another different type of fossil. In the case of a silicified clam, you are looking at an internal cast if you are looking at the inside of the shell, some of which contain muscle scars.
3) Just because the internal surfaces of shells of most clams are concave does not mean that all concave fossil surfaces can create casts similiar to casts of sculptures that are usual made with concave molds.
doushantuo 4,014
NOT the Gaffa
Location: sol 3
bivalve(Bambach,Am.J.Sc,1972)
bivalve(Crame,j.of Paleont.,2004)
ammonite(Macchioni,RIPS,2000):
Ediacara(Dzik,Int.Comp.Biol.,formerly called American Zoologist),2003)
Aha.. External mold, Internal mold, and Composite mold.
I guess the internal mold of a closed bivalve could be considered a cast of the critter that lived inside the shell... sort of But I agree that it is the internal part of the mold required to make a cast of the (hollow) shell.
Ludwigia 4,559
MOTM Jan. 2011; VFOTM 10/11; IPFOTM 03/12; 2013 IPFOTY
Editing Members
Location: Germany
On 1.8.2017 at 7:00 PM, Rocky Stoner said:
To mix things up a bit more, here is Merriam-Webster's definition.
20 hours ago, Ludwigia said:
Even paleontologists can use "cast" that way but if they include the word "internal", which that definition doesn't, then they don't mean steinkern unless someone can show me an example where one has. If you really want to mix things up there's always "endocast". Of course here the idea is to make a copy of what the brain looked like so it's still a copy of the original, therefore cast is correct, even though it's (mostly) convex and it's made against an internal surface but they still don't call it an internal cast.
An endocast is an unfortunate and confusing term of art. An endocast is an internal mold of the braincase and not a cast of a brain. An endocast does not show many details of what the brain looked like. An endocast of a human skull will not show all the folds and crenulations of our brains.
I'd like to add the following :
an "endocast" is useful in paleoneurology.
Your post COULD/might be misinterpreted as stating that important morphological details are missing from an "endocranial cast".
the "Museum handbook":
"What are molds and casts? A mold formed when the original fossil dissolved. This left a cavity within the surrounding rock. This negative impression preserves the external details of the original specimen. One rare form of mold can form when lava flows around a living tree. Tree molds are found at Craters of the Moon, El Malpais, and Lava Beds National Monuments. A cast is formed if this negative impression later filled with sediment. The cast may preserve all of the external morphological details of the original specimen but lacks any microscopic details. A steinkern is another type of mold. Steinkerns can result when a shell (such as a snail or clam) filled with sediment and then dissolved. The hardened sediment preserves a reverse image of the formerly hollow inside of the shell."
Coral(Leloux(Maastrichtian Scleractinia from the Netherlands,2004):
"Note on terminology A note on the use of the words positive, negative, steinkern, mould and cast in the context of fossil preservation is necessary. The skeleton of the coral is regarded as the original positive. The structure may or may not be diagenetically altered during life or before it is deposited in the sediment. When it is deposited in the sediment, most cavities of the skeleton can be filled with mud. The mud consolidated and the original skeleton is dissolved leaving a mould or negative. The fillings of the skeleton cavities are called steinkerns or internal moulds, being thus a special part of the mould. A cast would be the secondary filling of the mould by, for instance, calcite crystallization or new filling of mud and could be regarded as a secondary positive."
Go To Topic Listing Questions & Answers
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The Rising Tide Works as Documented
Thursday, May 24th, 2007 at 12:51 pm
It raises all boats, including, and especially, the poorest. (Via Captain Ed, because I don’t have a WSJ subscription.)
It’s been a rough week for John Edwards, and now comes more bad news for his “two Americas” campaign theme. A new study by the Congressional Budget Office says the poor have been getting less poor. On average, CBO found that low-wage households with children had incomes after inflation that were more than one-third higher in 2005 than in 1991.
The CBO results don’t fit the prevailing media stereotype of the U.S. economy as a richer take all affair — which may explain why you haven’t read about them. Among all families with children, the poorest fifth had the fastest overall earnings growth over the 15 years measured. (See the nearby chart.) The poorest even had higher earnings growth than the richest 20%. The earnings of these poor households are about 80% higher today than in the early 1990s.
A vibrant economy for all is a better long-term solution. Government taking a smaller percentage of peoples’ earnings give the poor more to spend and encourages investment by the rich which creates jobs. When government doesn’t encourage welfare, the poor, indeed, work, which is inherently better.
What happened? CBO says the main causes of this low-income earnings surge have been a combination of welfare reform, expansion of the earned income tax credit and wage gains from a tight labor market, especially in the late stages of the 1990s expansion. Though cash welfare fell as a share of overall income (which includes government benefits), earnings from work climbed sharply as the 1996 welfare reform pushed at least one family breadwinner into the job market.
Earnings growth tapered off as the economy slowed in the early part of this decade, but earnings for low-income families have still nearly doubled in the years since welfare reform became law. Some two million welfare mothers have left the dole for jobs since the mid-1990s. Far from being a disaster for the poor, as most on the left claimed when it was debated, welfare reform has proven to be a boon.
Far from throwing families out on the streets, welfare reform encouraged work. The work was there because the richer folks had money to start businesses or invest in them. The moral advantage of work over hand-outs should be self-evident. That doesn’t mean there should be no hand-outs, but policies that give families little incentive to work do not help them in the long run, no matter how it makes the policy makers feel in the short run.
More stats are discussed by the Captain.
Technorati Tags: Congressional Budget Office, economy, John Edwards, taxes, welfare reform, Ed Morrissey
The American Poor
Cruel to be Kind
Whom Would Jesus Indebt
Consider this quote:…
Filed under: Economics • Ethics & Morality • Government
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Daniel Henry George Sykes1
M, #590531, b. 15 October 1916, d. 3 September 1968
Daniel Henry George Sykes was born on 15 October 1916.1 He was the son of Sir Tatton Benvenuto Mark Sykes, 6th Bt. and Edith Violet Gorst.2 He married Bridget Walsh, daughter of Colonel Theobald Alfred Walsh, on 24 July 1964.1 He died on 3 September 1968 at age 51, without issue.1
He was a registered heroin addict.1
Philip Alan Bassett1
Last Edited=21 Oct 2018
Philip Alan Bassett was born in 1954.2 He married Elizabeth Conway Symons, Baroness Symons of Vernham Dean, daughter of Ernest Vize Symons and Elizabeth Megan Jenkins, in 2001.1 He died on 2 June 2018.2
He was journalist, with the Financial Times between 1978 and 1988.2 He was journalist, with the Times between 1990 and 1997.2
Child of Philip Alan Bassett and Elizabeth Conway Symons, Baroness Symons of Vernham Dean
Hon. James Alexander Bassett1 b. 1985
[S8647] Notices, The London Gazette, London, U.K.. Hereinafter cited as Financial Times.
Mary Freya Sykes1
F, #590533, b. 31 August 1904
Mary Freya Sykes was born on 31 August 1904.1 She is the daughter of Sir Tatton Benvenuto Mark Sykes, 6th Bt. and Edith Violet Gorst.2 She married Sir Richard Everard Augustine Elwes, son of Gervase Henry Elwes and Lady Winefride Mary Elizabeth Feilding, on 17 November 1926.1
From 17 November 1926, her married name became Elwes.
Children of Mary Freya Sykes and Sir Richard Everard Augustine Elwes
Jessica Mary Elwes+
Mary Freya Elwes+3 b. 1928, d. 15 Jul 1987
[S339] Descendants of William the Conqueror, online http://www.william1.co.uk/. Hereinafter cited as Descendants of William the Conqueror.
Henry Colborne Monck Ridley1
M, #590534, b. 1847, d. 7 March 1912
Henry Colborne Monck Ridley was born in 1847.1 He was the son of Maj.-Gen. Charles William Ridley and Hon. Henrietta Araminta Monck Browne.1 He married Emma Trueman, daughter of J. H. Trueman, in 1872.1 He died on 7 March 1912.1
Sir Richard Everard Augustine Elwes1
M, #590535, d. 4 September 1968
Sir Richard Everard Augustine Elwes was the son of Gervase Henry Elwes and Lady Winefride Mary Elizabeth Feilding.2 He married Mary Freya Sykes, daughter of Sir Tatton Benvenuto Mark Sykes, 6th Bt. and Edith Violet Gorst, on 17 November 1926.1 He died on 4 September 1968.
He held the office of High Court Judge.1 He gained the rank of Lieutenant-Colonel in the Northamptonshire Yeomanry.1 He was appointed Officer, Order of the British Empire (O.B.E.)1 He was awarded the Territorial Decoration (T.D.)1
Children of Sir Richard Everard Augustine Elwes and Mary Freya Sykes
Jessica Mary Elwes+2
Everilda Sykes1
Everilda Sykes was born on 17 November 1907.1 She is the daughter of Sir Tatton Benvenuto Mark Sykes, 6th Bt. and Edith Violet Gorst.2 She married Lt.-Col. Adrian Cuthbert Scrope, son of Henry Aloysius Scrope and Maria Mercedes de Laski, on 28 November 1928.1
Everilda Sykes also went by the nick-name of Petsy. From 28 November 1928, her married name became Scrope.
Children of Everilda Sykes and Lt.-Col. Adrian Cuthbert Scrope
Adrian Richard Scrope
Sarah Edith Mary Scrope+3
Christopher Ralph Scrope b. 17 Feb 1931, d. 21 Dec 2008
John Frederick Scrope+4 b. 1932, d. 10 Oct 2018
William James Conyers Scrope b. 1938
[S1122] Peerage News, online http://peeragenews.blogspot.co.nz/. Hereinafter cited as Peerage News.
Hon. Guy Robert Grimston1
M, #590537, b. 21 December 2011
Hon. Guy Robert Grimston was born on 21 December 2011.1 He is the son of James Walter Grimston, Viscount Grimston and Lady Rosanagh Viola Alexandra Innes-Ker.2
[S466] Notices, The Telegraph, London, UK. Hereinafter cited as The Telegraph.
Lt.-Col. Adrian Cuthbert Scrope1
Last Edited=11 Feb 2017
Lt.-Col. Adrian Cuthbert Scrope was born in 1906 at Kensington, London, England.2 He is the son of Henry Aloysius Scrope and Maria Mercedes de Laski.3,2 He married Everilda Sykes, daughter of Sir Tatton Benvenuto Mark Sykes, 6th Bt. and Edith Violet Gorst, on 28 November 1928.1
He gained the rank of Lieutenant-Colonel in the The Green Howards.1
Children of Lt.-Col. Adrian Cuthbert Scrope and Everilda Sykes
Adrian Richard Scrope4
Christopher Ralph Scrope6 b. 17 Feb 1931, d. 21 Dec 2008
William James Conyers Scrope4 b. 1938
[S1042] Peter Wood, "re: Persse Family," e-mail message to Darryl Lundy, 26 February 2003 to 2019. Hereinafter cited as "re: Persse Family."
Hester Tyrrell1
F, #590539, b. 5 May 1656
Hester Tyrrell was baptised on 5 May 1656 at Thornton, Buckinghamshire, England.2 She was the daughter of Sir Toby Tyrrell, 2nd Bt. and Lucy Barrington.1
[S4567] Bill Norton, "re: Pitman Family," e-mail message to Darryl Roger LUNDY (101053), 6 April 2010 and 19 April 2011. Hereinafter cited as "re: Pitman Family."
[S474] FamilySearch, online http://www.familysearch.com. Hereinafter cited as FamilySearch.
Sir Peter le Maire1
M, #590540, d. January 1632
Last Edited=7 Mar 2019
Sir Peter le Maire married Hester Tyrrell, daughter of Sir Edward Tyrrell, 1st Bt. and Elizabeth Kingsmill, on 12 January 1631 at Leckhampstead, Buckinghamshire, England.1,2 He died in January 1632.1
[S7529] WikiTree, online http://www.wikitree.com/. Hereinafter cited as WikiTree.
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TSX INTEL REPORT: The Int’l Swimming League is half over; have you noticed? + Tokyo gets a refund for moving the marathons & walks & Jepkosgei upsets Keitany in NYC Marathon
Rich Perelman
≡ TSX INTELLIGENCE REPORT ~ 4 November 2019 ≡
● LANE ONE ● Is the International Swimming League making an impact? It doesn’t appear to be making money …
The International Swimming League is on a break from its first four meets – two in the U.S. and two in Europe – and will resume on 16 November.
Did you know that it was happening at all?
The attendance has been modest, especially at the two U.S. meets, in Indianapolis and in the Dallas area, and a little better – meaning more than 1,000 per day – in Naples, Italy and Budapest, Hungary.
The television production is good in some respects, but overheated in others, and the “set” is always dark outside of the pool itself, with heavy graphics to obscure the small crowds.
But the athletes love it. They’re the stars of a heavily-produced show, with the names and images shown life-size or bigger on multiple video screens and they are (1) getting paid well by swimming standards and (2) are part of a team which has its travel expenses covered, so that they aren’t out of pocket.
But without fans in the stands, modest viewership on television and no sponsors that can be discerned, the $4 million-plus cost of the league is on founder and financier Konstantin Grigorishin of Ukraine.
Now, he’s a billionaire, so he might decide to keep this going for a long time. But is it making an impact?
Not only has the fan response been modest in terms of revenue, the ISL is not even the most important thing to the swimmers participating. During one of the many coach interviews in the show from Dallas, L.A. Current coach David Marsh said on the air what everyone in the sport knows: that his choices of which swimmers are entered in which events is subject to their training priority, which is to get ready for the 2020 Olympic Games, or in some cases, national Olympic trials.
That’s a problem. The ISL’s fight with FINA has receded for the moment, but the federation would be well served to help ISL wherever it can, but having a program like ISL is already helping it. How? More here.
● TOKYO 2020 ● Tokyo government concedes marathons and walks move to Sapporo, but could get a big refund
The International Olympic Committee, spooked by the sight of marathoners dropping in the Doha heat at the IAAF World Championships in late September and early October, has moved the men’s and women’s marathons and the three race-walking events from Tokyo to Sapporo in 2020.
It did so without prior consultation with the Tokyo Metropolitan Government, which is paying for a significant part of the 2020 Games and set off a diplomatic incident with Tokyo Governor Yuriko Koike that came to a head in last week’s meetings with the IOC’s Coordination Commission.
The outcome was fairly predictable, and the Tokyo government conceded that the IOC has the legal right to move the events, even nine months prior to the 2020 Games. But Koike hardly came away empty-handed.
She got a promise that no more events will be moved, which is hardly good news for the open-water swimmers and triathletes, who endured brutal conditions during their 2019 test events. She also got the agreement of the IOC to relieve the Tokyo government and the Tokyo 2020 organizers of the costs of putting on these races – including the media infrastructure – and of any expenses already incurred in the planning, which “cannot be used elsewhere.”
Koike’s political party estimated the total expenses of putting on the races in Sapporo at up to $310 million, meaning her agreement might save her government and the organizers as much as $100 million. Not bad! More here.
● ATHLETICS ● First-timer Jepkosgei upsets Keitany to win New York City Marathon
The annual TCS New York City Marathon was held Sunday and was expected to be a celebration of a fifth win for Kenyan star Mary Keitany. It didn’t work out that way.
Keitany was in good form and broke from the pack after about 20 miles, but she had company: the world-record holder in the Half Marathon, fellow Kenyan Joyciline Jepkosgei, who had won the New York City Half Marathon earlier in the year, but making her marathon debut.
At about 22 1/2 miles, Jepkosgei took off and Keitany could not respond. On a cool and clear day, perfect for distance running, Jepkosgei finished in 2:22:38, the second-fastest time in race history, with Keitany 54 seconds behind. Including a big time bonus, Jepkosgei won $145,000 on the day.
The men’s race was similar, but it was 2017 winner Geoffrey Kamworor of Kenya who was full of run and broke away after mile 23 and won easily. His time of 2:08:13 was 23 seconds ahead of countryman Albert Korir. Third was Ethiopia’s Girma Bekele Gebre, who was not among the elite field and started at the front of the regular runner pack. He set a lifetime best of 2:08:38 and won $55,000, including a $15,000 time bonus. More here.
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Zagitova, 17, was upset by 16-year-old fellow Russian Alena Kostornaia, in her first season on the senior level, 236.00-216.06. Kostornaia won both the Short Program and Free Skate, while Zagitova fell to third in the Free Skate behind a lifetime best performance from American Mariah Bell, who remained in third overall.
Russia went 1-2 in Pairs, with Anastasia Mishina and Aleksandr Galliamov winning the Free Skate to take the overall victory from Short Program leaders Daria Pavliuchenko and Denis Khodykin, 207.58-206.56. Americans Haven Denney and Brandon Frazier were third.
More here and here.
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The U.S. was eliminated, losing to Senegal, 4-1; tying Japan, 0-0, and losing 4-0 to the Netherlands. Scores and schedules are here.
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The next-to-last meet in the 2019 FINA World Cup was held in Kazan (RUS) over the weekend, with Hungary’s Katinka Hosszu once again the individual star, but not the points leader.
The race for points, based on wins and the quality of an athlete’s best race, determines who wins the big bonus payments for the final two-meet cluster and for the final overall standings, which pays $150,000-100,000-50,000 to the top three in each gender.
Hosszu won the 200 m Fly and both medleys and was the only swimmer with three individual victories. But Australian rival Cate Campbell won two events and finished second in another, but had the best performance according to the FINA Points table and leads the women’s points standings with 57. Fellow Aussie Kayle McKeown also won two events and had the third-best performance to score 45, wile Hosszu got no performance bonuses and sits at 36.
In the men’s division, Russian Anton Chupkov won two Breaststroke events and had the fastest performance for 48 points, leading Dutch star Arno Kamminga (36) and perennial World Cup scoring leader Vladimir Morozov (33).
The World Cup will finish up next week in Doha (QAT), with Morozov to be crowned the men’s overall winner and Campbell holding a 24-point edge over Hosszu and nearly sure to win as well. More here.
● SCOREBOARD ● Roberts win BMX Freestyle Park World Cup; Valente takes four medals in Track Cycling
The winter seasons are coming alive, not only on ice and snow, but also in cycling and fencing, which are starting their World Cup programs.
In Chengdu (CHN), the final BMX Freestyle World Cup was held, with American Hannah Roberts winning both the event and the seasonal World Cup title, followed by teammate Perris Benegas, the reigning World Champion.
In Minsk (BLR), the first UCI Track Cycling World Cup was held, with American Jennifer Valente (pictured) putting on a show. She won her specialty, the Omnium, but also scored victories in the Points Race and Team Pursuit with three teammates. She also picked up a bronze in the Scratch race.
Italy’s Filippo Ganna scored two world records in the men’s Individual Pursuit, taking the mark down to 4:04.52 in the qualifying and then to 4:02.647 in the final. Dutch sprinter Harrie Lavreysen won three events, taking the Sprint, the Team Sprint and Keirin.
At the USA Luge National Championships, Summer Britcher won her second straight title and Jonny Gustafson his first in a weather-shortened program of one day and two runs.
There’s much more with reports on Badminton ~ Beach Volleyball ~ Cycling ~ Fencing here, and on Freestyle Skiing ~ Luge ~ Snowboard ~ Short Track here.
● THIS WEEK ● U.S. women start new era, swimming World Cup ends in Qatar
There’s a lot of action coming up this week, including the first games for the U.S. women’s National Team under new coach Vlatko Andonovski, vs. Sweden in Colombus, Ohio on Thursday (7th) and Costa Rica on Sunday (10th) in Jacksonville, Florida.
The FINA Swimming World Cup will conclude in Doha (QAT), while the first of USA Swimming Tyr Pro Swim Series comes in Greensboro, North Carolina (yes, they overlap!).
American Hannah Roberts will be the favorite in the UCI Urban Cycling Championships in Chengdu (CHN) in the BMX Freestyle Park, a debut event for the 2020 Olympic Games. Previews coming later this week.
Albert Korir
Alena Kostornaia
Alina Zagitova
Anton Chupkov
Cate Campbell
Evan Bates
FIFA men's U-17 World Cup
Filippo Ganna
FINA Swimming World Cup
Gabriella Papadakis
Geoffrey Kamworor
Girma Bekele Gebre
guillaume Cizeron
Hannah Roberts
Harrie Lavreysen
IOC Coordination Commission
ISU Figure Skating Grand Prix
Jennifer Valente
Jonny Gustafson
Joyciline Jepkosgei
Katinka Hosszu
Konstantin Grigorishin
Madison Chock
Mary Keitany
Perris Benegas
Summer Britcher
U.S. Women's National Team
UCI Freestyle Park World Cup
UCI Track Cycling World Cup
Vladimir Morozov
Vlatko Andonovski
Yuriko Koike
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by MadCapsule on Fri Jun 02, 2006 9:33 pm
My local Best Buy was sold out, so I went to Borders and it actually turned out to be a couple bucks cheaper.
MadCapsule
by raasnio on Fri Jun 02, 2006 9:41 pm
Hollywood_Bob wrote: I bought mine at Target last night...I do know that not all BB stores carry the same merchandise so that is what you may have run into
The one near my house has had problems in the past where the computer shows they have it in stock but they cannot find the item anywhere. They never have this problem with major titles, just the odd ones.
I went to Target and picked it up.
raasnio
by Chairman Kaga on Fri Jun 02, 2006 10:28 pm
I should grab this before DVDuesday.
by Keepcoolbutcare on Fri Jun 02, 2006 11:31 pm
more quotes! (yes, I'm fucking obsessed with this show!)
Dean: "I dare you to make less sense!"
Dean: "Good thinking, bro'a'mine. And I thought I was supposed to be the smart one."
Hank: "Ma Venture didn't raise no fools..."
Dean: "W-We don't have a mom, Hank... "
[awkward silence]
The Monarch: "I wanted to thank you for finding Grover Cleveland's presidential time machine for me. I'll give him your regards."
Dr. Thaddeus Venture: "I pissed in God's eye - and He blinked."
Hank: "Wuss!"
Dean: "Knock it off!"
Dr. Thaddeus Venture: "Boys! for the last time, stop! Brock is trying to drive."
Brock: [to boys] "I'm cool."
Hank / Dean: [at each other] "He started it!"
Dr. Thaddeus Venture: "No, I started it years ago in a moment of passion, and I'll end it the same way, right here, in front of Brock, H.E.L.P.eR., and God!"
by Chairman Kaga on Wed Jun 14, 2006 11:34 pm
OK I picked up this DVD and I was wondering if anyone else noticed any audio problems with theirs. I noticed on only one epsiode for a very short time (like half a sentence) the audio simply disappears. Has anyone read anything about a faulty production with these like that BTTF realease a while ago with the wrong aspect ratio. Also is it infantile of me that I want the audio to be uncut instead of bleeped out swearing?
Which episode?
No, it's not infantile of you to want the audio uncut.
To whinge about it here tho'...
by Chairman Kaga on Thu Jun 15, 2006 1:10 am
I'll have to rewatch them. It's on the first disk and it's while the Monarch is talking in his lair.....The audio just drops out of his sentence.
by Keepcoolbutcare on Sat Jun 17, 2006 7:24 am
so, after watching each episode 4-5 times already, the completist dork in me had to listen to a commentary track. Hardly verbatim, but here goes...
Doc - referring to Dr. Girlfriend - "I'm so hot, I'd do me!"
Publick - "What guy would you do?"
Doc - "You know, I want it on the record I haven't thought about this outside of right now. But, if I had to choose...Dean."
by Bean on Sat Jun 17, 2006 10:09 am
Oh I haven't watched it with commentary yet... I'll throw it in after work.
by Leckomaniac on Sun Jun 18, 2006 4:22 pm
So Moriarty posted his review of the Venture Bros. Season 1 up on the main site. I posted his words below. He seems to share the same feelings as the rest of us.
Moriarty wrote: Awesome.
This is one of those times where I ignored everyone’s recommendations to see this show. I tried to watch five minutes towards the end of an episode, and it just irritated me. I never gave it another chance until I got back from my trip recently and found this at the top of a fairly formidable stack of waiting DVDs. That cover... that great iconic skull image... finally tipped me over and I had to check it out. I told myself I’d watch one episode, start to finish, and see what I really thought of it. And that one episode... well, that’s all it took.
This show is crack. I could watch another five seasons of it tomorrow if the DVDs were available. I’ve actually watched the full 13 episode run twice now. Jackson Publick and Doc Hammer (great names for both of those guys, eh?) are the creators of this crazy, beautiful series. It looks like this was originally designed to be a parody of JONNY QUEST and little else, but sometimes, things take on a life of their own, and this show evolved over the course of that first season into something much richer than a simple goof on another series. It’s got a rhythm and a style all its own, and a cast of characters that are so fucking bizarre that I would watch them do pretty much anything.
The Venture Brothers are Hank and Dean, but they’re hardly the stars of the show. I’d say their father, Dr. Rusty Venture, is more important to the series than they are. He was raised by his world-famous scientist father, and he spends every day trying to live up to his father’s reputation. All the pills he pops probably don’t help, and he can barely stomach his own sons as a result of his self-loathing. He’s more richly written than most live-action characters, to be frank.
And it can’t help that he spends all his time with Brock Samson, his bodyguard, who is like the most hyper-masculine exaggeration of macho I’ve ever seen. Voiced by Patrick Warburton, Brock Samson is one of the greatest comic characters in recent memory. In fact, overall I’d say this is the best Adult Swim show since the creation of AQUA TEEN HUNGER FORCE, and I think it’s actually a bit better as a show. ATHF makes me laugh like a crazy person, but THE VENTURE BROS. works better as a show for me. I like the universe they’re creating, the characters that fill out the edges of the world. I think The Monarch is a great arch-enemy, and Dr. Girlfriend cracks me up. I love Baron Underbheit. I love the way the JONNY QUEST cross-over was handled. I love Dr. Orpheus and his Hot Topic-addicted daughter Triana. I think it’s brilliant the way they fold in pop culture to this show, subtle in a way that Seth McFarlane can only dream of. What other show on TV would have an episode in which The Six Million Dollar Man and Sasquatch are on the run together, Dumbledore lovers marked for destruction by a government that doesn’t understand their love?
Warner Home Video has put a fair amount of extras on the disc, including some commentaries, deleted scenes, the original pilot, the Christmas special, and more. The reason to buy the disc, though, especially if you haven’t already seen the show, is for these episodes. Just check out the titles, which totally convey the pulpy feel of the show: DIA DE LOS DANGEROUS!, EENY, MEENY, MINEY... MAGIC!, RETURN TO SPIDER-SKULL ISLAND. Great stuff.
My one question is about the ending of the final episode from season one. Makes it hard to do a season two, doesn’t it? Still, we’re about a week away from the premiere of the second season, so I guess we’ll see how they handle it then.
by Hollywood_Bob on Sun Jun 18, 2006 4:25 pm
personally, I still crack up every time I see the brothers in the aquaman and spiderman PJs...kills me
by RogueScribner on Sun Jun 18, 2006 6:20 pm
I love this show, it's definitely the best thing on AS right now. I have to make do with watching it on TV for now though, since I'm not exactly swimming in dead presidents at the moment.
by Kilgore on Mon Jun 26, 2006 1:01 am
Season 2 started tonight - did not miss a beat.
No spoilers until some of you get to see it...suffice to say it was awesome - new title sequence and everything.
I couldn't tell for sure, but it looks like Brock lost his mullet, he's wearing hats the whole episode.
by Keepcoolbutcare on Mon Jun 26, 2006 1:17 am
Kilgore wrote: Season 2 started tonight - did not miss a beat.
I watched it on Friday, 'cuz I loathe TV and, well, I had nothing better to do ...
it didn't measure up to my hopes, but what could? thought the intro was brilliant, but then it kinda dragged for a while, though the reason for King Gorillas incarceration was fucking hysterical. But then, just when the little lady said she wouldn't be watching if the boys didn't return, the utterly hysterical montage of their 14 previous demises, my faves being "gas, the silent killer" and the look of pure joy on Dean's face as he's running with the scissors.
Can't wait for next weeks "Hate Floats".
by Hollywood_Bob on Mon Jun 26, 2006 2:47 am
Friggin Hillarious....time to put them back in the oven....HA HA HA....so damn good....
by Roybertito on Mon Jun 26, 2006 3:45 am
This is better than last season. If you didn't watch it, watch the rerun on Thursday, it was great.
-Roy, Animation Addict
"Is it fear or courage that compels you, boy?" - Megatron, TRANSFORMERS (2007)
Roybertito
Location: My chair.
by silentbobafett on Mon Jun 26, 2006 5:31 am
QUESTION: Over here in Blighty I have no idea what the fuck Venture Bros is! Well, I did some research. So its animation. Its comedy.
Is this some cartoon where is funny cos some guys beats people up alot and a couple of guys get into jams each week. Oooohhhh the adventure.
Or/and does it have quality, deep characters with decent written gags as well as visual ones. ala Simpsons (I know the basis is very different - but I'm talking with regards to the depth of comedy and charaters) I find it very hard to get into TV animated cartoons cos they are either shit (too many to mention) rip offs (Family Guy - and it really ain't that funny!) or just wish it was live action cos they aren't taking advantage of the medium!
Now Venture Bros sounds exciting, I almsot brought hte DVD from my DVD site - but htey were sold out! But someone said something above which scared me: "....before Brock laid some violence on them"....
I'm up for violence and slap stick etc but if that is the height of the gags on this thing... I'll skip it!
What say you? Convince me to buy! Or stop me... your are in control.... oohhh ahhhhh eeeeeeee
silentbobafett
Location: In The Night Garden...
^No, there are some great gags in this. For example, in tonight's episode, the boys' "zombies" were walking around the lab and Dr. Venture, who is stuck in a predicament where half of his body is in a wall and half is stuck in the TV due to a malfunctioning teleporter which was made by his twin brother Jonas Venture Jr. who was stuck inside of Dr. Venture until Dr. Venture became pregnant with him, released him, and was attacked by him, tells his bodyguard Brock Sampson to "put them back in the oven," and Brock says, "I can't touch them, they feel like giant Stretch Armstrongs."
Just watch it.
by unikrunk on Mon Jun 26, 2006 6:16 am
Good lord that was fantastic; I love the flashbacks with the mechanic working on the teleporter.
Oh, and the flashbacks of all the other, um...Venture family deaths.
/Ready for more
by stereosforgeeks on Mon Jun 26, 2006 2:47 pm
Man what a great episode.
I loved the monarch / king gorilla prison rape joke.
"Wait is this even my cell? Did you take me back to your place?"
"Yea... Ive got porn here. It helps"
by RogueScribner on Tue Jun 27, 2006 12:34 am
I missed it. Grrr.
by John-Locke on Tue Jun 27, 2006 10:02 am
I've watched all the episodes over the last few days, it's not always hysterical but it's got a lot to admire, it takes about 4 or 5 episodes to get going and establish the dynamic and then it's as good as any other adult animation out there, it's constantly building on the continuity of previous episodes and is all the stronger for it, the first episode of series 2 is probably the strongest because of this, seeing the henchmen out of costume, the Monarch still in prison etc just tickles my funny bone.
Glad I finally got around to seing this show, Love it.
John-Locke
BULLETPROOF TIGER
by The Garbage Man on Tue Jun 27, 2006 8:10 pm
Ditto. I finally got to watch the episode last night and was a little disappointed until the death montage. The changing hairstyles, the variety, the facial expressions, the casualness about the whole thing, it was just note-fucking-perfect.
With more fans, more money, and more support from the network methinks we're in for a treat this season.
Oh, and? Brendon Small doing voicework for the show! Here's hoping that wasn't just a one-time thing.
The Garbage Man
Location: The Big Blue Velour Marble
RogueScribner wrote: I missed it. Grrr.
http://www.adultswim.com/adultswimfix/index.jsp
Adult Swim Fix is airing it all week...YAY!
Locke, glad to have you aboard.
by Kilgore on Tue Jun 27, 2006 9:39 pm
I can't decide whether my favorite line was 'If you have an accident-prone kid, you make him wear a helmet...' or simply the Monarch screaming 'You Assholes!' when no-one showed to help him escape.
There is so much good here.
Kilgore wrote: I can't decide whether my favorite line was 'If you have an accident-prone kid, you make him wear a helmet...' or simply the Monarch screaming 'You Assholes!' when no-one showed to help him escape.
"You eviscerated and sodomized Vince Neal on national television!"
"Hey, I only sodomized half of him...they wanted the Surreal Life, KG GAVE THEM THE SURREAL LIFE!".
The Monarch had better bust KG out, if only so the big fella can assrape Phantom Limb...
Agreed, I would also like to see more of 'White Noise'
by Chairman Kaga on Tue Jun 27, 2006 11:04 pm
MadCapsule wrote: My local Best Buy was sold out, so I went to Borders and it actually turned out to be a couple bucks cheaper.
BTW MC I never thanked you for mentioning Borders in here. I originally checkd my local Best buy and Circuit City to no avail until I remembered what you posted and found it at Borders.
by raasnio on Tue Jun 27, 2006 11:11 pm
The first ep of Season 2 was an excellent way to kick things off. This is still he best thing on Adult Swim. 8)
by mushookie on Wed Jun 28, 2006 2:07 am
Hillarious as hell, I loved the way they broguht them back!
I can't wait for those new episodes, Korgoth episodes, nor Pee-Wee's Playhouse
mushookie
Location: The land where Alice Cooper's "Frankenstien" will never be fed.
by Keepcoolbutcare on Fri Jun 30, 2006 8:51 pm
Hate Floats is on the Fix right now, if anybody feels like watching...
by The Garbage Man on Fri Jun 30, 2006 9:16 pm
I can never get the thing to play reliably, but let us know how it is if you watch it.
If anyone hasn't seen the new VB season 2 commercials, they reveal that Hank's Batman costume will return, which delights me to no end.
Doesn't he say, 'I'll see you in heck!'
by The Garbage Man on Fri Jun 30, 2006 11:39 pm
You're right, he does! That makes it even better.
Incidentally,
Jackson Publick, by way of his blog, wrote: For those of you who bought the Venture Bros. Season One DVD, there is a "lost commentary" available for download at quickstopentertainment.com. We always knew there'd only be room for about four or five episode commentaries on the set, but we recorded a few extra ones as we worked out our various sound problems and tried to tried to acclimate ourselves to the idea of talking at our computer for 22 1/2 minutes. Also to give Adult Swim a variety to choose from. If you liked the commentaries on the DVDs, this is more of the same kind of fast and loose crap.
Just for giggles, below are the titles of all of this season's upcoming episodes, in roughly the order they're to air. Figured I'd beat adultswim.com to the punch for once (titles and running order subject to last minute change, as is our habit):
"Powerless in the Face of Death"
"Hate Floats"
"Assassinanny 911"
"Escape to the House of Mummies"
"20 Years to Midnight"
"Victor. Echo. November."
"Love-Bheits"
"Fallen Arches"
"Guess Who’s Coming to State Dinner?"
"I Know Why the Caged Bird Kills"
"¡Viva los Muertos!"
"Showdown at Cremation Creek"
Venture Bros. Possibly the Best half hour on TV
by bastard_robo on Sat Jul 01, 2006 6:03 am
watched hate floats,
GOD I FUCKING LOVE THIS SHOW, but a little nit pick, you can tell the animation is being done by someone else, it jsut throws me off a bit.
by raasnio on Sun Jul 02, 2006 11:03 pm
Hate Floats was hilarious. This season is going to be even better than the 1st.
by unikrunk on Tue Jul 04, 2006 9:56 am
I think Hate Floats is my new favorite episode, for so, so many reasons. The jump suit, Brock and Phantom Limb's strange respect for each other, the new henchmen...fuck, I could go on all day.
Simply brilliant.
by John-Locke on Tue Jul 04, 2006 10:09 am
The bit at the beginning with the henchmen humming the dramatic music had me laughing like a giddy schoolgirl, one of the greatest episodes yet, this show just gets better and better.
by unikrunk on Tue Jul 04, 2006 10:14 am
@JL - Punching in the pass code on the non-existent keypad to 'gain entry' to his closet...oh fuck...I have a hard time breathing even thinking about it.
by Chairman Kaga on Tue Jul 04, 2006 10:06 pm
John-Locke wrote: The bit at the beginning with the henchmen humming the dramatic music had me laughing like a giddy schoolgirl, one of the greatest episodes yet, this show just gets better and better.
I loved that since it was Holst's Mars- Bringer of War from his ochestral suite The Planets which has been used alot in film. Great episode.
by Chairman Kaga on Fri Jul 07, 2006 12:56 am
What happened to Brock's mullet?
by Leckomaniac on Fri Jul 07, 2006 2:03 am
Ugh. I keep missing the new Venture Bros. I tend to fall asleep early on Sundays because of work. And I keep trying to remember to watch on Thursdays...but it slips my mind.
I need Tivo.
by raasnio on Fri Jul 07, 2006 3:57 am
Leckomaniac wrote: Ugh. I keep missing the new Venture Bros. I tend to fall asleep early on Sundays because of work. And I keep trying to remember to watch on Thursdays...but it slips my mind.
You don't need Tivo. You aren't supposed to like Venture Bros. anyway. I love that show.
by unikrunk on Fri Jul 07, 2006 7:38 am
Chairman Kaga wrote: What happened to Brock's mullet?
>in Brock voice<
Burned off when I was chained to the car, last season.
You can tell I'm growing this beauty out again though...so..
Thank you! That was killing me. Can anyone name any of the films that's been used in?
Question about "Hate Floats"...doesn't Dr. Girlfriend claim she doesn't drive? But in the first scene of "Tag Sale--You're It" she's driving the #'s 21, 24 and the Monarch to the Venture compound.
Good ep, my fave bit was the sign "Henching - The Coolest Career Ever".
Yes, it's on now. No, I won't share my thoughts...
by The Garbage Man on Fri Jul 07, 2006 9:04 pm
I believe she says, "I don't drive men." Good catch, kcbc. Don't know what that's about, other than that in the bonus audio commentary, Doc and Jackson admit to not coming up with a plan or really talking through characters, rather each just kind of does his own thing.
If you haven't checked it out, that audio track (linked above) is pretty good. They talk more about the show's origins and more behind-the-scenes stuff rather than just pointing out what's happening onscreen at the moment (something that irked me about the first commentary). Especially interesting is how The Monarch evolved - before The Venture Bros., they had written a script involving Aquaman and Black Manta as roommates, and their take on Manta lead to The Monarch.
The Garbage Man wrote: If you haven't checked it out, that audio track (linked above) is pretty good. They talk more about the show's origins and more behind-the-scenes stuff rather than just pointing out what's happening onscreen at the moment (something that irked me about the first commentary). Especially interesting is how The Monarch evolved - before The Venture Bros., they had written a script involving Aquaman and Black Manta as roommates, and their take on Manta lead to The Monarch.
yeah, I've been meaning to get over there and give that a look.
Assassinanny, even viewed on the Adult Swim site, has some of the best animation I've seen on the show yet.
"1/2 Swedish, 1/4 Polish, 1/4 Winnebago"
"Manaconda!"
Lots of Molotov, some great Brock backstory and a final act chock filled with so many popculture references it'll make your head spin.
by papalazeru on Sat Jul 08, 2006 12:23 am
Just witnesseed Series 2 episode 2. Am going back to watch the rest.
Has a hell of a lot of promise as a geek comedy show.
by Keepcoolbutcare on Sat Jul 08, 2006 6:48 pm
papalazeru wrote: Just witnesseed Series 2 episode 2. Am going back to watch the rest.
what's really neat is that for a seemingly non-sequitor filled, popculture referencing cartoon, they pay a lot of attention to continuity, to giving the season an arc. As the Garbage Man said, Publick and Hammer didn't really intend for things to go that way, but sometimes fiction takes on a life of it's own.
And as Locke said above, while it took him about 5 episodes from season 1 to get really into it (I was hooked from the get-go), it pays off big time.
So start at the beginning Papa, a lot of the self-referential jokes that you might've missed jumping in at season 2 will be explained.
And glad to have you on board as well.
GO TEAM VENTURE!
by Kilgore on Sat Jul 08, 2006 7:10 pm
For the record, I kinda like that Brock's mullet is gone this season, it's a good change of pace - now he has a blonde Lee Majors/Robert Urich as Dan Tanna style going. Hopefully for season three he'll go with a 'stache and feather the hair, ala Lee Horsely as Matt Houston.
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Characters, Minor Characters, Unknown Gender
The worm as it appeared in "Evicted!"
Worms are first seen extremely briefly in “Tree Trunks” in which they make a cameo appearance trying to eat an apple. They make another cameo appearance in “The Enchiridion!” in which they are in the trees when Finn steals a giant’s dollar. In “Evicted!” a worm is on Finn’s bed, squiggling along and making a radio wave sound like “Wowowowowowowo”. Finn tells it “No worms on the bed!” and throws a book at it so it falls off. Many more worms were seen in the Tree Fort later in the episode in which Giant Worm King is there. It is unknown whether there, although there is a worm king, a Worm Kingdom.
Retrieved from "https://adventuretimewithfinn.fandom.com/wiki/Worms?oldid=4613"
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Return to Feature Stories
Permanent link to this article: https://advocacyforfairnessinsports.org/feature-stories/ncaa/
Breaking Down the NCAA’s Latest Stall Tactic for Athlete Compensation
In September of this year, California enacted a law that would allow college athletes to profit off their name, image, and likeness (NIL) beginning in 2023. The NCAA vehemently opposed this law and even threatened that any California schools that allowed their student athletes to profit off their NIL would be in violation of NCAA rules and therefore unable to compete against NCAA teams.
Nebraska Senator Megan Hunt Calls Upon Experience In Fighting For College Athletes’ Rights
Megan Hunt is a first in several ways. She is not only the first woman to represent her district in Nebraska’s unicameral legislature but the first member of the Nebraska Senate from any district who is also openly bisexual. The 33-year-old Democrat is also about to become the first Nebraska Senator to propose a bill that would allow college athletes in the state to profit off their names, images and likenesses without it affecting their eligibility to participate in NCAA athletics.
What the Aspen’s Insitute’s Panel on NIL Legislation and a 1974 Chart-Topper by America Have in Common
On Tuesday, Dec. 17, some of the most notable voices in college athletics came together to discuss NIL legislation at the Aspen Institute in Washington, D.C. The whole conversation misses the mark in a big way, however, that is perhaps prophetically interpreted by the band America in their 1974 hit, “Tin …
SB 206 Would Benefit More Athletes Than the Narrative Indicates
Somehow the narrative around SB 206, and athlete rights to the name, image, and likeness of their birthright—a right that every other American citizen takes for granted is being distorted in the media–both as to what it is and the number of athletes it would benefit.
Easley and Finnerty may blow wide open the ‘dam’ that Ploetz ‘cracked’
The legacy of Ploetz v. NCAA is playing out in two similar trials, both with very similar claims. If as successful as Ploetz was, the consequences for the NCAA along with its member conferences/institutions could be serious.
Irv Eatman: It’s All About the Student-Athlete. Or is it?
It has been over four decades since I entered college at UCLA. I really enjoyed being a student/ athlete but I would be lying if I said there were not times when it was very difficult. Trying to balance school, practice, travel, games and yes socializing was not easy. Fast forward to present day and as the father of a soon to be student/ athlete, things have not gotten any easier.
The business of college football has produced its own version of human trafficking
An Interview with Robert Green October 22, 2017
Derek Helling Every year, the passage of another college football season spans from August through January, and the economic machine keeps thousands of people in industries from foodservice to retail apparel busy. As with most businesses of this scale, there are stories …
Why are we still treating college athletes as less than human?
In 1857, the Supreme Court of the United States of America acted as the mouthpiece of a society which clammored for the reinforcement of economic traditions along with class and race barriers. In 2018, the NCAA fills much of the same role in its adjudication of similar duties. With the convictions of Christian Dawkins, James Gatto and Merl Code Jr. on the charges of conspiracy to commit wire fraud and wire fraud in a Manhattan federal court in late October
The Pullman labor battles of 1890s live on in college athletics today
The phrase, “those who don’t learn from history are doomed to repeat it” has become cliché and that unfortunately means it has lost much of its meaning. Considering the status quo involving NCAA athletes who play revenue sports, it’s unfortunate how little society learned from a similar situation in the 1890s which historians refer to as the Pullman strike.
As March ends, the ‘madness’ in D1 basketball continues
A new NCAA D1 men’s basketball champion will be celebrated on Tuesday, April 3 and going forward throughout the year, but it’s not difficult to look around and see outside of the cavalcade of names on championship banners from year to year, not much else has changed in the game. A recent study by Jason Belzer and Eli Boettger for Athletic Director U highlights the fact that the industry of coaching collegiate basketball is still stuck in the mid-20th century. The study claims to reveal discrimination in the coaching ranks that is not only prevalent but institutionalized.
Loss of value insurance programs progressing but work remains
As the prevalence of loss of value insurance policies among NFL prospects who are preparing for a career as a professional athlete in the NCAA ranks grows, the current state of the industry appears to be trending upward while some issues are still lingering.
Feature Stories Mind of Maurice Clarett MLB/MiLB CFL Domestic Violence & Sexual Assault in Sports Esports Financial Fraud Health Legislation NBA/WNBA NCAA NFL Soccer Olympics Youth Sports
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A. H. Richardson
Jorie and the Magic Stones, Jorie and the Gold Key, Jorie and the River of Fire, Murder in Little Shendon & ACT ONE, Scene One – Murder, Murder at Serenity Farm
Jorie and The Magic Stones
Jorie and the Gold Key
Jorie and the River of Fire
Murder in Little Shendon
ACT ONE, Scene One — Murder
Murder at Serenity Farm
Murder on Baringo Island
Interview with @seranopressone
November 21, 2017 November 21, 2017 / A. H. Richardson / Leave a comment
via The Hazlitt/Brandon Series of Murder Mystery Novels by A. H. Richardson (Author Interview) @seranopressone
Welcome to another brilliant interview here on Always Trust In Books. I have A. H. Richardson here to answer some questions about her murder-mystery series. I am a huge mystery fan so it was a nice to have an author to chat with about a new series. The Hazlitt/Brandon novels sound really good, a world war two setting is intriguing and I am looking forward to seeing how Richardson has incorporated it into a quality mystery novel. First a few details about the novels and A. H. Richardson, then on to the questions!
The Hazlitt/Brandon Series of Murder Mystery Novels by A. H. Richardson
The Hazlitt/Brandon series of murder mystery novels follows a pair of clever, colorful and charismatic sleuths – Sir Victor Hazlitt and Beresford Brandon – as they scratch their heads searching for clues to figure out whodunit.
The first book in the series, Murder in Little Shendon, is a thriller murder mystery which takes place in a quaint little village in England after World War Two.
Picture, if you will, a picturesque village called Little Shendon, suddenly caught up in dealing with a murder of one of its citizens — not a particularly well-liked one at that. Which makes it all the more intriguing because the list of suspects becomes very long. This tantalizing tale unfolds with twists and turns to find out whodunit to Mr. Bartholomew Fynche, the murdered shopkeeper.
Fear grips the community as the investigation slowly progresses. Everyone is interviewed; everyone is suspect! From his housekeeper to Lady Armstrong and her household staff. Or could it be the shy librarian new in town? Or the defiant retired army major and his lady-friend, the post mistress? Or perhaps the weird sisters who live on the edge of town? Then there is the couple who own the local inn and pub, along with the two Americans who are staying there? Even the vicar and his wife fall under the gloom of suspicion.
Uncertainty, wariness, and terror reign as neighbors watch neighbors to discover the evil that permeates their upturned lives. No one feels safe in this charming little village. Who is the murderer? And why was this strange uncivil man dispatched in such a seemingly civil community?
A murder mystery that will keep you reading until you learn the details, uncovered by Police Inspector Stanley Burgess and his two amateur detectives, Sir Victor Hazlitt and Beresford Brandon. The three sift methodically through the Alibis and life stories of the suspects until they uncover…
You are challenged to discover the culprit before the last few pages. And no fair looking ahead — it’s the journey that proves the most enticing.
The Q&A Section
Thank you for taking some time to answer questions about your murder mystery series! Could you tell us a little bit about yourself?
You are so welcome. I was born in England during World War Two of an opera-singing mother, and a very famous composer father, Clive Richardson. I trained as an actress and graduated from LAMDA, went to work in an office, was a model for a fur coat company, adored horses, and rode a lot. I was an only child, and grew up with directors like David Lean, A. Hitchcock, etc. all friends of my father’s who was writing music for film.
Could you share your own personal overview of the Hazlitt/Brandon series?
I think from an early age I had wanted to write books, for children, and some for the ‘older children’ in the form of murder/mysteries. Sir Victor Hazlitt, whom I love because he is wise and cautious, and a ‘smoothie’ without being a ‘smartass’ (can I say that?) Well, I said it… sorry. His immediate opposite is Beresford Brandon, a teddy-bear of a man with great emotions, a true gourmand, a romantic soul, a Shakespearean actor and somehow they work perfectly together. Having created these wonderful fellows, I had to find mysteries to put them in, and they came very easily.
I love a great whodunit! How long had you been planning to write this series?
Not long really … I tend to work fast, and never have writer’s block, I get just the opposite of WB, and I’m not sure what that is called! After Vic and Berry appeared, I started writing immediately, and was surprised at how easily their first story came together. I think that my years of acting, theatrical background, and some of those genes from my father did not hurt me!
Is it difficult to manage two lead characters working alongside each other?
No, not at all. They play off each other so well, and I try to see that they remain ‘who they are’ throughout. Consistency is enormously important, and once I let them play together, they write the book… not me! Hard to explain.
How long does it take to finish a book from starting a draft to the finished book?
I should say around three and a half months.
How many books have you already planned to include in the Hazlitt/Brandon series?
Another one is on its way called ‘Murder on Baringo Island’
Could you give us some insights into what challenges you faced when writing a post-war murder mystery?
It’s easier to write books in that time period… one doesn’t have to worry about computers, and DNA and other things… it’s all done the old fashioned way, with clues and red herrings and AHA moments, such fun!
How do you usually celebrate after you have finished writing a book?
I jump up and down and shout ‘YES!’ and then I do it again. I do actually dance around to some rock n’roll, and then I always ask myself ‘ Now, how did you do that?’ I don’t know the answer to that – I see everything in pictures and images, and then I write what I see … make sense?
Murder mystery is one of my favorite genres. What attracted you to the genre?
I think it goes back to solving puzzles, who did this? How was it Done? Why was it Done? And the murder(s) give it some excitement.
What do you do to wind-down from all the writing?
Watch an old movie, feet up, with three dogs at my side, two pugs and one thug (who happens to be a 5-month old baby English Bulldog) – We’re both English, so we get on really well!
Have you read a book recently that you would personally recommend to the readers of this blog?
Here goes old fashioned me: Get a classic like Jane Eyre, and re-read it, it takes one to another world, and that’s always good — for a little while.
‘O What a Tangled Web we Weave’
March 8, 2015 March 8, 2015 / A. H. Richardson / Leave a comment
‘Oh What a Tangled Web They Weave
When Dragons practise to Deceive…
February 21, 2015 February 21, 2015 / Michele Richards Design / Leave a comment
Snuggled up with a good dragon and trying to keep warm – how ’bout you? Stay warm and safe, and don’t go out unless you absolutely have too …counsel from the Great Grootmonya …coming soon to children near you …
Purchase on Amazon.com
Purchase on Barnes & Noble.com
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Category Archives: A – Kindness
Kindness shares video for Robyn-aided “Who Do You Love?”, announces US tour dates
UK singer Adam Bainbridge, aka Kindness, returns today with a video for his Robyn collaboration, “Who Do You Love?”. Directed by Daniel Brereton, it features portraits of both singers’ family and friends. Explained Bainbridge, “This video and this song is about people and connection, and how you can identify who you are by those you love. Those people say a hell of a lot about you.”
Additionally, Kindness has announced the first batch of 2015 tour dates in support of his recently released sophomore album, Otherness. The itinerary includes a few dates in February, but really picks up in March, with additional shows still to be announced. Watch the video and see the current tour schedule below.
Kindness – Who Do You Love feat. Robyn
Kindness 2015 Tour Dates:
01/16 – London, UK @ Electric Brixton
02/25 – Los Angeles, CA @ El Rey
02/28 – San Francisco, CA @ Mezzanine
03/05 – Portland, OR @ Doug Fir
03/06 – Seattle, WA @ Neumos
03/07 – Vancouver, BC @ The Biltmore Cabaret
03/08 – Calgary, AB @ Commonwealth
03/10 – Minneapolis, MN @ Triple Rock
03/11 – Chicago, IL @ Lincoln Hall
03/13 – Toronto, ON @ Wrongbar
03/14 – New York, NY @ Bowery Ballroom
03/15 – Brooklyn, NY @ Rough Trade
03/18 – Cambridge, MA @ The Sinclair
03/19 – Washington, DC @ U Street Music Hall
Leave a comment Posted in A - Kindness Tagged collaboration, Daniel Brereton, indie pop, indie rock, Kindness, music video, North American tour, tour dates, UK singer Adam Bainbridge, video
Kindness, ‘Otherness’ – Awesome!
Posted by Unruly Hearts on October 21, 2014
Kindness’ new album, Otherness, available now.
Pooneh Ghana/Courtesy of the artist
It takes audacity to name your debut album after the seismic Eddie Kendricks song “Girl You Need A Change Of Mind,” a seven-minute soul classic with an extended breakdown and build-up that made it one of the earliest disco records. But the lanky Brit Adam Bainbridge had a firm grip on his influences for 2012’s World, You Need A Change Of Mind, an album that touched not only on disco, but also on ’80s boogie and R&B, Frankie Knuckles-indebted house music, D.C. go-go, and even The Replacements (with a dance remake of “Swingin’ Party”).
Bainbridge doubles down on that ’80s sound for Otherness. “New feelings we begin again / Old endings we begin anew,” he sings in “World Restart,” which from its compressed drum machine to its honking saxophone sounds like a lost track from 30 years ago. Midway through, he’s joined by fast-rising R&B singer Kelela, who sounds like one of the Mary Jane Girls circa 1983’s “All Night Long.” But the feelings behind the song revive those staid sounds and make them sound refreshed.
From there, Kindness pulls from various earmarks of that era, be it the go-go bells that power “This Is Not About Us” or the elegant piano that flows through “I’ll Be Back.” Rapper M.anifest joins in for “8th Wonder,” name-checking Tracy Chapman’s “Fast Car” in his verse. And when Kelela returns in “With You,” the track at one point peels back to a synthesized breath, a brief homage to Art Of Noise’s classic single, “Moments In Love.”
Much like his musical compatriot (and fellow Brit) Devonté Hynes did on Blood Orange’s sublime Cupid Deluxe, Bainbridge draws on assists from friends. Beyond the album highlights with Kelela, the sputtering backbeat, rubbery slap-bass line and church organ of “Who Do You Love?” gets a big lift from Swedish singer Robyn, who infuses the song with her pop effervescence. Hynes himself lends a hand in “Why Don’t You Love Me,” which evolves from a heartbreaking ballad to sensuous R&B to great effect. It hints that Kindness might change and advance yet again.
Kindness – Otherness
Kindness – House
Leave a comment Posted in A - Kindness Tagged "Otherness", Adam Bainbridge, available now, Eddie Kendricks, Kindness, new album
Kindness (Adam Bainbridge) – “Otherness” OCT 13 UK / ROW / OCT 14 N. AMERICA
Kindness is the solo project of British singer Adam Bainbridge. His debut album, World, You Need a Change of Mind, co-produced by Philippe Zdar was released on 16 March 2012.
In 2007, Adam Bainbridge was a recipient of the Eric James Johnson Memorial Fellowship, at The Philadelphia Institute for Advance Study.
Live in Philly was Adam Bainbridge’s contribution to the Eric James Johnson Memorial Fellowship program. It consists of an album recorded during his stay at the Institute in May 2007, and a small pamphlet illustrating the work, typeset by hand. Employing a variety of musicians from the Institute and the rest of Philadelphia, as well as sound sources and records found or recorded in the city, the Kindness album is a personal and welcome contribution to the Institute’s body of work.
—The Philadelphia Institute for Advance Study,
Live in Philly was released in 2007 as a free MP3 download and CDr, with no label.
In 2009, Moshi Moshi Records released Kindness debut single Swingin’ Party. Gee Up was included on the vinyl b-side and a VHS video directed by Jack Latham accompanied it.
In October 2011, Cyan was released as a limited edition 12″ vinyl through Kindness’s own record label Female Energy in the UK and Terrible Records in North America. The B-side contained 3 unnamed lock grooves.
Kindness’s debut album, World, You Need a Change of Mind, co-produced & mixed by Grammy Award-winning producer Philippe Zdar was released on 16 March 2012. Live sessions were recorded for Radio 1‘s Zane Lowe and Rob da Bank as well as 6Music’s Lauren Laverne, Live from Maida Vale. Kindness also played the iTunes Festival 2012.
In 2013, Kindness contributed to production and instrumentation on Blood Orange’s Cupid Deluxe.
As a live band, Kindness has performed at a number of festivals and headline shows through the world including South by Southwest, Latitude Festival, Printemps De Bourge, Sydney Opera House, Primavera Festival, Field Day Festival, Eurockennes, Calvi on The Rocks, Oya Festival, Way Out West, Flow Festival, Summer Sonic, Bestival, We Love Green, Les in Rocks Festival, Midi Festival, and Soulwaxmas.
In May and June 2013, Kindness supported The xx as part of their Night and Day Festival in London and Berlin.
Adam Bainbridge has directed and co-directed a number of videos for his own Kindness project as well as for other artists, including Grizzly Bear, Blood Orange, and William Onyeabor:
Adam Brainbridge of Kindness
Grizzly Bear “Don’t Ask” (Final Fantasy Version) Adam Bainbridge
Kindness “Gee Up” Adam Bainbridge
Kindness “House” Adam Bainbridge & Dan Brereton
Kindness & Trouble Funk “That’s Alright” Adam Bainbridge
Kindness “36 Hours in the Go-Go Scene” Adam Bainbridge & Pauline Beaudemont
Blood Orange “Chamakay” Adam Bainbridge
William Onyeabor “Fantastic Man” Adam Bainbridge & Camilla Wasserman
Blood Orange “Uncle ACE” (Kindness remix) Adam Bainbridge
World, You Need a Change of Mind (16 March 2012)
Otherness (13 October 2014)
“Swingin Party” (28 September 2009)
“Cyan” (26 October 2011)
“SEOD” (8 February 2012)
“Gee Up” (16 March 2012)
“House” (15 June 2012)
“That’s Alright” (21 September 2012)
“Blood Orange – Uncle Ace” (Kindness remix feat. Robert Owens) (10 April 2014)
“Röyksopp & Robyn – Monument” (Kindness remix feat. Busiswa) (15 August 2014)
To pre-order the album:
ITUNES / AMAZON / KINDNESS
Leave a comment Posted in A - Kindness Tagged Adam Bainbridge, Kindness, new album announcement, october 2014 release
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What more can be said of the late, great Gram Parsons? He's been dubbed everything from "the inventor of Country Rock" to "the godfather of Alt Country" and "a goddamn pussy." (Those last words actually came from Merle Haggard.) Whatever your take on him is, Parsons can be credited for fusing the boogie strut of rock 'n' roll with sweet Soul melodies, uplifting Gospel-influenced harmonies and (above all) the broken hearted sentiment of country music. He influenced everyone from the Rolling Stones to the Eagles to Wilco and beyond. He called Waycross, Georgia his homeland and attributed his love for country music to his upbringing in the South. Parsons' earliest recordings were rooted in folk, however. After playing in a number of Kingston Trio sounding Folk Revival troupes, he tried his hand at some Fred Neil influenced Singer/Songwriter work before giving life to the International Submarine band, arguably the first electric Country Rock band. Soon after releasing the then innovative "Safe At Home" on Lee Hazlewood's LHI label, he was recruited by the Byrds to record "Sweetheart of the Rodeo" with them. He turned their country music flirtations in a new direction that crossed Nashville West with his International Submarine Band (If it were not for Roger McGuinn, "Sweetheart of the Rodeo" might not have sounded like a Byrds record.) He then recruited the Byrds' Chris Hillman from to form the Flying Burrito Brothers, a rhinestone clad quartet of psychedelic Country Rockers. Parsons then abandoned ship to hang with the Stones, discover Emmylou Harris, and cut two prodigious solo albums that blended Bakersfield country influences with Boogie Rock and Honky-Tonk. Parsons died shortly after from a morphine 'n' tequila overdose in room #8 of the Joshua Tree Inn at the age of 26 without one hit single to his name. Eric Shea
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Música Americana Cósmica
What more can be said of the late, great Gram Parsons? He's been dubbed everything from "the inventor of Country Rock" to "the godfather of Alt Country" and "a goddamn pussy." (Those last words actually came from Merle Haggard.) Whatever your take on him is, Parsons can be credited for fusing the boogie strut of rock 'n' roll with sweet Soul melodies, uplifting Gospel-influenced harmonies and (above all) the broken hearted sentiment of country music. He influenced everyone from the Rolling Stones to the Eagles to Wilco and beyond. He called Waycross, Georgia his homeland and attributed his love for country music to his upbringing in the South. Parsons' earliest recordings were rooted in folk, however. After playing in a number of Kingston Trio sounding Folk Revival troupes, he tried his hand at some Fred Neil influenced Singer/Songwriter work before giving life to the International Submarine band, arguably the first electric Country Rock band. Soon after releasing the then innovative "Safe At Home" on Lee Hazlewood's LHI label, he was recruited by the Byrds to record "Sweetheart of the Rodeo" with them. He turned their country music flirtations in a new direction that crossed Nashville West with his International Submarine Band (If it were not for Roger McGuinn, "Sweetheart of the Rodeo" might not have sounded like a Byrds record.) He then recruited the Byrds' Chris Hillman from to form the Flying Burrito Brothers, a rhinestone clad quartet of psychedelic Country Rockers. Parsons then abandoned ship to hang with the Stones, discover Emmylou Harris, and cut two prodigious solo albums that blended Bakersfield country influences with Boogie Rock and Honky-Tonk. Parsons died shortly after from a morphine 'n' tequila overdose in room #8 of the Joshua Tree Inn at the age of 26 without one hit single to his name.
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About the Arbitration Law Database
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Murphy Exploration & Production Company – International v. Republic of Ecuador, UNCITRAL, PCA Case No. AA434 - Journal of Damages in International Arbitration, Vol.3 No.2
Jamie Miller
PCA,
UNCITRAL,
PDF723.58 KB
Originally from Journal of Damages in International Arbitration
I. FACTUAL BACKGROUND
A. Contractual History
In 1987, Claimant Murphy Exploration & Production Company (“Murphy”) acquired an indirect 20% interest in a Service Contract for Block 16 in Ecuador (the “Service Contract”) through two of its wholly-owned subsidiaries: Murphy Ecuador Oil Company Limited (“Murphy Ecuador”) and Canam Offshore Limited (“Canam”). The Service Contract was originally executed the prior year between a consortium of foreign investors (the “Consortium”) and the predecessor of Petroecuador, Ecuador’s State-owned oil company. Under the Service Contract, the Consortium earned a fee for exploration and development of Block 16 but did not take a share of any of the oil produced (rather, Petroecuador retained all production). Shortly before the relevant events giving rise to this dispute, Canam assigned its interests in the Consortium to Murphy Ecuador.
The Consortium first discovered oil in Block 16 in 1987, and production began thereafter in December 1994. By the following year, it was clear to Ecuador that the sale of produced oil would be insufficient to cover the costs owed to the Consortium under the Service Contract. This was true in Block 16 as well as in other Blocks where Petroecuador had entered into similar service contracts with other foreign companies. In response, Ecuador sought to convert its existing service contracts into participation contracts where contractors would earn a share of production instead of a fee for their services. Ecuador believed this model would incentivize contractors to efficiently produce oil by keeping costs low while producing the maximum amount of reserves.
Ecuador passed legislation throughout the 1990s to facilitate the conversion to participation contracts, including Law 44, which amended the Hydrocarbons Law specifically to allow for participation contracts. In tandem, it passed legislation to attract foreign investment to its hydrocarbons industry. In December 1997, Ecuador passed the Investment Promotion and Guarantee Law (known as “Law 46”) to “promote national and foreign investment and to regulate the rights and obligations of the investors so that they may effectively contribute to the economic and social development of the country.” Ecuador also amended its Constitution to guarantee foreign investment the same treatment as national investments.
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Chevron Corporation and Texaco Petroleum Corporation v. The Republic of Ecuador, UNCITRAL, PCA Case No. 2009-23, Chevron Post-Hearing Letter on BIT Proceedings in Chevron v Donziger et al (June 1, 2015)
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More by Jamie Miller
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Archbishop awards St. Joseph Medal of Appreciation to 129 worthy parish volunteers
Archbishop Leonard P. Blair shakes hands with Margaret Calamita of St. Ambrose Parish in North Branford and awards her the St. Joseph Medal of Appreciation during a ceremony on March 31 at the Cathedral of St. Joseph in Hartford. One of 129 volunteers honored for exemplary service, Calamita currently volunteers as a funeral ministry leader, lector and Alpha Team member for her parish. (Photo by Aaron Joseph)
Story by Shelley Wolf
Pastors know they could never run their parishes without the hard work of committed parish volunteers. That’s why more than 100 priests turned out on March 31 to congratulate the many volunteers who were recognized with the St. Joseph Medal of Appreciation at the Cathedral of St. Joseph in Hartford.
Archbishop Leonard P. Blair awarded 129 parish volunteers — including individuals and married couples — drawn from 131 parishes and quasi-parishes for their commendable service.
The cathedral was filled to overflowing with the medal recipients, the pastors who nominated them for special recognition, and the honorees’ family and friends.
Each year, recipients give of their time and talent to enhance their parish communities in numerous ways. Many have volunteered in multiple capacities over the years. Some have served for decades.
Archbishop Blair, the principal celebrant at the daytime prayer service, thanked the honorees, invited everyone to join him in adoration of the Blessed Sacrament, then blessed the Saint Joseph medals and awarded the recipients. At the conclusion of the service, the honorees were invited to have their photos taken with the archbishop.
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Daniel Nyiri
Daniel Nyiri, Owner, Founder and CEO
Daniel Nyiri is an entrepreneur and the Owner, Founder and CEO of 4U Fitness with one goal: to revolutionize the fitness industry.
Born in Budapest, Hungary, Daniel started his career as a professional hockey player, model and certified personal trainer. He moved to the United States in 2011 with $150 and a dream to change the world through improving the health of others one person at a time.
Understanding how much work and capital is needed to build a business, Daniel worked five jobs to generate income and develop the right relationships so he could begin his entrepreneurial career. He developed the American version of E-Fit, the full-body electrical muscle stimulation workout, with Dr. Janos Papp, which catapulted his success.
He worked diligently to save enough money to purchase a small fitness studio for $30,000. This studio would become 4U Fitness. Daniel soon found his next passion in life, Nina Tamez-Mendez. Now Nina Nyiri, Daniel considers her his other half and supportive partner for life. A Master Trainer and Lifestyle Coach, Nina is now the Head of Trainer Education for 4U Fitness and is holds a key role in the company’s brand development. With Nina, E-Fit, and extensive knowledge within the topics of health and fitness, Daniel has built a client base of professional athletes, Olympians and celebrity models, turning a barely-making-it business into a $1 million enterprise within two years.
In 2014, Daniel obtained FDA 510(k) clearance for E-Fit making it the only full-body EMS machine with that status in the United States. This became the final element to complete his formula for guaranteed, proven results for the everyday person.
For Daniel, it isn’t about the money but about “building a real company that adds and contributes to this world, just as Steve Jobs, Walt Disney and Henry Ford did.” Daniel believes that by creating a company that stands for something more, we are building a legacy that will reshape the future.
Today, 4U Fitness has been featured in various notable publications including Entrepreneur Magazine, Tampa Bay Times, Business Observer, Oxygen Magazine, and Men’s Journal.
Recently Daniel was featured in the Movie Generation Iron 2 which was in theaters in 2017 with Arnold Schwarzenegger and now its available on Netflix.
Follow Daniel on his Live Show: “The Journey of an Entrepreneur” here!
Now an Amazon Best Selling Author for FitBiz: Secrets of a Seven-Figure Gym
Whether you own a gym, a personal training studio or you are thinking about getting into the fitness industry, FitBiz is designed for you. Daniel Nyiri’s very own guide to running an efficient and scalable gym, FitBiz will show you the tools to implement so your business is profitable, sustainable and a strong brand that clients can trust. Get it on iBooks, Barnes & Noble, Amazon, Audible and Amazon Kindle today!
Men’s Journal
CBS TV
MindBody Interview – Powering Rapid Growth
Dynamic Lifestyle Podcast – Coming to the US with $150 and a Dream to End Obesity
Gym Owner Monthly Magazine Feature
DowntownStPete.com
Ideamensch Interview
The Doctors TV Show
“From $150 to a 7- Figure Gym” Loud Rumor
Jobs in Sports
The Fitness Business Podcast
Gym Owners Monthly Magazine (78-79)
On The GSD Show with Mike Arce
That Business Show 2.0 – Entrepreneurship
Simpli Faster Blog
FSLOCAL Blog Interview
Anatomy of the Perfect Hire by Jobvite
How To Make Your First Million by Chicago Tribune
That Business Show with Jamie Meloni
I Love The Burg
Everup.com
That Business Show
Voyage MIA Feature
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Montana Morning State News Headlines for Tuesday, October 2
Peter Christian
Missoula man who fell asleep at the wheel in 2017 and killed an eight year-old girl, appeared in court in a petition to revoke his suspended sentence over the issue of restitution.
Missoula Justice Courts to become 'courts of record', and both Justices of the Peace Holloway and Beal support the change, saying it will help crime victims and save taxpayers money.
Lt. Governor Mike Cooney says to be wary of an RNC fundraising letter that could be confused as being from the U.S. Census Bureau. The letter asks for political contributions.
Sunny and mild in western Montana today, with highs in the low to mid 50's.
Categories: Missoula News
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Nigeria Does Not know if it Wants to be a Socialist or Capitalist Country- By Yomi Kazeem
Nigeria’s government often struggles with the idea of a free market.
On one hand, it woos investors about the potential of doing business in Nigeria but on the other, it often tries to dictate how their businesses should be run.
This week, the example of DStv, the South-Africa owned pay TV company in Nigeria, proves that point as Nigeria’s Consumer Protection Council (CPC) secured a court ruling stopping DStv from increasing prices this month as planned. CPC claims that the move is part of an investigation over consumer complaints including DStv’s “arbitrary pricing.” The CPC says it is also investigating DStv for signing exclusive agreements with content providers and making it harder for competitors to offer premium content as well as the possibility of the company intentionally increasing prices in Nigeria to “compensate” for losses in other African markets.
Protesting the price.
But here’s the thing: regulating prices does not fall within the CPC’s remit and premium content is often sold exclusively in regions by the broadcast rights holders. ”It’s regulatory overreach,” says Nonso Obikili, an Abuja-based economist. “We have government agencies who try to do things that are beyond their mandate. Sometimes it’s to extract rent but sometimes, it’s just because they can.”
Notably, the CPC’s actions have been backed by many Nigerians who have long accused DStv of charging too much. Essentially, a bulk of Nigeria’s middle-class wants to watch premium television content but also decide how much they want to pay for it. The DStv example is not in isolation as through a mix of aggressive regulators, government interventions and lobbying by the elite, middle-class and unions, Nigeria has a history of favoring practices that are anathema to free markets.
Take petrol, for example. Nigeria’s government has fixed prices private gas stations and importers must sell the product—even though the economics do not add up. Nigeria’s lack of working refineries means that Africa’s largest oil producer cannot refine its biggest export. To cater to local demand, it must import refined petrol while exporting crude. But despite the fluctuations in global oil prices and import costs, the government does not allow flexible pricing. The result is a recurring gas shortage crisis—especially around Christmas—as importers protest shortened profit margins. Rather than deregulate the petroleum industry and allow prices change based on competition and market forces, the government has a corrupt history of funding billion dollar subsidies to keep fixed prices in place. But the government isn’t the only culprit in this regard as Nigerians have also repeatedly pushed back against any petrol price increases.
There are also instances when the government has also batted against foreign airlines for “discriminatory fares that disfavour Nigeria” and threatened to withdraw their licenses. And back in 2016, as a response to dwindling reserves, Nigeria opted for stiff currency control policies as it restricted access to dollars and put limits on how much foreign exchange Nigerians could spend abroad. The policy proved costly: airline companies shut down or cut back operations citing difficulties repatriating dollar profits.
The tendency to try to control private enterprise is “part of the general idea that people are not free to do things unless the government gives the go ahead,” Obikili tells Quartz. “It’s an idea that’s ingrained in the Nigerian economy.” That’s a sentiment shared by Cheta Nwanze, a researcher with SBM Intelligence, a Lagos-based intelligence consulting firm. Shunning free market policies, he argues, is ”a mixture” of both populism and badly thought out economic policy as “fixing prices follows no laws of economics.” Given the prevailing reality, significant and consistent business success in Nigeria largely depends on securing either government patronage or intervention.
Crucially, the government seemingly reserving the discretion to determine prices in a free market conflicts with its rhetoric about improving the ease of business and attracting investment. ”These things send signals,” Nwanze tells Quartz. “And signaling is extremely important in the corporate world.”
Yomi Kazeem
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Davido Splash N36 million On Customized Jewelry for Zlatan
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Answers Universe
Quick Answers To Random Questions
How did Edgar Allan Poe die?
December 14, 2019 by Pamela Landy
In October 1849, the forty-year-old writer Edgar Allan Poe was found lying unconscious near a polling place in Baltimore.
According to some reports, he had been fed liquor and dragged to various polling places to vote repeatedly.
He was taken to a hospital where he remained semicomatose for three days.
On October 7, 1849, at 3 A.M. he died of “congestion of the brain” and possibly intestinal inflammation, a weak heart, and diabetes.
What detective did Edgar Allan Poe invent?
What was the first in the series of films produced by Roger Corman that were inspired by the works of Edgar Allan Poe?
Is Edgar Allan Poe's The Narrative of A. Gordon Pym (1838) based upon actual events?
What is Edgar Allan Poe's epitaph?
How many times does Edgar Allan Poe's Raven say "Nevermore"?
How long was J. Edgar Hoover in charge of the FBI?
Filed Under: Literature
About Pamela Landy
Pamela Landy loves to answer questions.
About · Privacy · Contact
Copyright © 2020 Answers Universe
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https://apnews.com/PR%2520Newswire/0a8690eee038f09ea0bce1c38894218b
Global Luxury Real Estate Membership Community REALM™ Begin Onboarding First Members
REALM Founder Julie Faupel welcomes new Founding Partner Brennan Buckley to REALM.
NEW YORK, Jan. 7, 2020 /PRNewswire/ -- REALM™ begins onboarding elite real estate professionals to its unique membership-based global luxury community this month with a strong platform in service to real estate professionals at the highest level. REALM Founder Julie Faupel together with Katie Brockman, Chief Revenue Officer/Group Publisher Luxe Interiors + Design announced a dynamic partnership between the two luxury brands providing proprietary online content to members of the REALM community.
REALM is the luxury real estate technology community that is founded and inspired by leading luxury real estate professionals across the globe to leverage human connections and power agent productivity in the luxury sector through networking and insight. REALM offers members and their clients access to listings, elite global events, experiences and resources such as proprietary content and intelligence with the sole mission of adding unmatched value to the agent relationships.
“The global luxury real estate category is a multi-trillion dollar industry,” says Faupel. REALM was created by a consortium of the finest luxury professionals in this industry who recognize service to clients as their highest goal. Customizable content is a key aspect of the value of membership in REALM, and we could not have found a stronger partner than the creative team at Sandow.”
“We are thrilled to announce a new and innovative content partnership with REALM crafted to deepen the agents’ relationships with their clients,” says Brockman. “By harnessing our deep knowledge of architecture + design and combining it with our editorial expertise, we will create engaging, curated content filled with a diverse range of articles from Luxe.”
“Each story will be sharable,” says Faupel, allowing real estate professionals to customize the content to suit the various passions of their clients—encouraging conversation, exploration and discovery. Luxe and REALM both understand how critical customization is in today’s market. We know this presents a huge value to our members.”
In addition to the dozens of monthly stories relevant to the real estate, design and style industries, REALM members will have access to actionable and undeniably powerful intelligence from sources including Wealth X, the global leader in delivering the most respected data on the world’s wealthiest individuals available today.
REALM founding partner, Gary Gold of Hilton & Hyland, last month sold Chartwell, California’s most expensive home, listed at $198 million in Bel-Air. “To be able to manage all the opportunities we have is the biggest challenge of any real estate agent who is successful,” says Gold. “Besides my own sphere of influence, I get more business from agents than any other source. REALM has given me a new tool to meet the people I don’t know. When you take REALM’s artificial intelligence and then apply human intelligence to that, there is money to be made.”
Joining with Faupel to help develop this depth of REALM’s powerful impact on its members is industry leader Brennan Buckley. As a REALM Founding Partner, Buckley joins the leadership team from Iowa Realty, a Home Services of America company, where he most recently served as president during his nearly 15 year tenure with the firm.
“What is compelling about REALM,” says Buckley, “is that we offer our members the highest level of support available today by harnessing the power of global relationships with the most sophisticated economic intelligence available. Our members have direct access to over three million profiles of high net worth and ultrahigh net worth individuals from over 190 countries around the globe.”
REALM is the brainchild of Founder, Julie Faupel, owner of Jackson Hole Real Estate Associates, a past winner of Christie’s International Real Estate Affiliate of the Year award in 2011 and 2014.
Working with a team of strategic global real estate and technology leaders, investors and visionary futurists, Faupel tasked Silicon Valley engineers to create a unique curated luxury lifestyle software integrating Machine Learning and Artificial Intelligence that aggregates and secures data improving the holistic real estate experience for real estate professionals and their clients with the highest degree of security and privacy.
Early adopters and collaborators with REALM include real estate professionals and industry leaders from across the U.S. led by agents from Brown Harris Stevens, Strand Hill Properties, Richardson Properties, Hilton & Hyland, Slifer Smith and Frampton and Landvest. Real estate professionals who share Faupel’s industry changing vision can inquire about REALM membership at https://www.realm-global.com to learn more.
About REALM
REALM is the first-ever collaborative, lifestyle-matching venture in real estate that enables its member-agents to greater productivity and relationship enhancement through the power of data. REALM connects discerning clientele and their advisors through a patent-pending matching platform and bespoke experiences customized to enhance relationships. REALM uses an “open” platform, which will work with various CRMs to optimize members’ client lists while working in a secure, encrypted environment. To learn more, go to https://www.realm-global.com
About Luxe Interiors + Design
Luxe Interiors + Design is the unrivaled regional architecture + design authority. Built upon the unique platform of being both globally inspired yet locally sourced—currently spanning 14 local editions as well as delivering nationally—Luxe reaches a highly discerning audience of design aficionados. Speaking to this coveted audience in their home markets, while also covering national and international design trends, Luxe has become the fastest growing brand in the shelter category today. It boasts a total distribution of 550,000 and recently added Southeast and Naples editions to its network. Published by SANDOW, a leader in innovation and design.
About Sandow
Sandow is a fully integrated solutions platform that includes leading content, tools, and services for the design industry. Its portfolio of assets includes Interior Design Media, Luxe Interiors + Design and Galerie Media, as well as research/strategy firm, ThinkLab.
MEDIA CONTACT: Terri Tiffany, Terri@SandHillPRPartners.com 650 387-7720
View original content to download multimedia: http://www.prnewswire.com/news-releases/global-luxury-real-estate-membership-community-realm-begin-onboarding-first-members-300982256.html
SOURCE REALM
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https://apnews.com/PR%2520Newswire/ce5e74570fa87d4e580ba5e9bddeb0d0
Parts Town launches local OEM parts marketplace “Parts In Town”
ADDISON, Ill., Jan. 15, 2020 /PRNewswire/ -- Parts Town, a leading foodservice equipment parts distributor, today announced the initial launch of its latest innovation, Parts In Town. This industry first e-commerce marketplace is designed to enable customers to access local inventory of genuine OEM (original equipment manufacturer) parts enabling improved equipment up-time and performance. This innovative approach to marketplace technology allows local service companies and distributors to display their OEM parts inventory on partstown.com and benefit from the massive amount of traffic on the most utilized foodservice parts website in the world. Ultimately, Parts In Town makes OEM parts more visible and available than ever before bringing benefits to manufacturers, service companies, distributors, and operators.
“We are really excited about Parts In Town. At Parts Town, we have a deep commitment to industry innovation and a passion for making genuine OEM parts accessible faster than ever before,” said Steve Snower, Chief Enthusiasm Officer, a.k.a. CEO, of Parts Town. “We are also particularly excited about what this technology and program enables, because it brings unique benefits to local service companies and distributors, allowing them to benefit from the traffic on partstown.com to help them grow their parts sales and expand their customer base.”
Parts In Town is the latest in a long line of industry firsts created by Parts Town, which includes the industry’s most utilized website and mobile app, as well as several unique features. The company recently announced the launch of an enhanced version of “techtown,” an online community for technicians across the industry to share best practices, get answers to their questions, and access helpful information. Emanuela Delgado, VP of Innovation at Parts Town states, “We are always looking for new ways to innovate and support the foodservice industry, our manufacturer and customer partners. With Parts In Town and techtown, we are creating programs that are part of a broader strategy and commitment to supporting businesses doing critical service work in commercial kitchens every day.”
The initial launch of Parts In Town took place in Q4 2019 with full ramp-up coming in the first half of 2020. To learn more about Parts Town and Parts In Town, visit www.partstown.com and follow updates on Facebook, LinkedIn, Instagram and Twitter.
About Parts Town
Parts Town is a leading distributor of genuine OEM (original equipment manufacturer) foodservice equipment parts. When there’s a hiccup in any commercial kitchen, Parts Town is ready to jump in and help with the most in-stock parts on the planet, innovative technology, and an unmatched customer experience. Customized solutions benefit food equipment service companies, chain restaurants, institutions and independent restaurants.
Parts Town leads the way in industry innovation. Its Serial Number Lookup tool uses model serial number level detail from a variety of foodservice equipment manufacturers to create a more precise search and order process for buying replacement parts for commercial kitchen equipment. The 360-degree imaging technology, PartSPIN®, valuable interactive diagrams, convenient Smart Manuals, and the industry’s first mobile app allow customers to easily and conveniently find and view equipment manuals and parts in the field, where that info is needed most. These innovations, paired with same day shipping and extended hours of operation, ensure the correct part is ordered and delivered every time.
Partnering with the top manufacturers of commercial cooking, refrigeration, ice and beverage equipment and more, Parts Town improves the supply chain, increases sales of genuine OEM parts and keeps every customer’s business running like clockwork.
Parts Town has been recognized for its company’s growth including 11 consecutive years of making the prestigious INC. 5000 list as well seven placements to Crain’s Chicago Fast 50 list.
Parts Town makes finding and buying foodservice equipment parts easy, fast and kinda fun.
View original content to download multimedia: http://www.prnewswire.com/news-releases/parts-town-launches-local-oem-parts-marketplace-parts-in-town-300987168.html
SOURCE Parts Town
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Briefing Complete in Kisor
Post by Alan Horowitz
The petitioner has now filed his reply brief in Kisor, and the case is fully briefed in preparation for the oral argument later this week on March 27. Given the government’s partial retreat from defending Auer deference (see our prior post here), which the petitioner describes as a “sharp retreat,” the reply brief responds to two different briefs. First, it responds directly to an amicus brief by a group of law professors (linked in our prior post) that put forth a full-throated defense of Auer deference. Second, it acknowledges that the government’s “Auer-light” position is “preferable to existing Auer deference,” but it still rejects that position and argues that complete overruling of Auer is the correct approach. The reply brief concludes that the existing principles of Skidmore deference satisfactorily address the policy goals described in the government’s brief without improperly permitting “an agency to exert its expertise in binding fashion without any participation by the regulated public.”
Kisor – Petitioner Reply Brief
Filed under Administrative Law, Kisor, Regulatory Deference, Supreme Court / Tags: Administrative Law, Auer deference, Kisor, Regulatory Deference
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The Tax Appellate Blog is intended to be a resource for information on important tax cases under consideration in the appellate courts. It will feature insightful commentary on the issues and provide a dedicated site for following the progress of these cases.
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is a Member of the Supreme Court and Appellate Litigation Group at Miller & Chevalier and has successfully briefed and argued six cases at the U.S. Courts of Appeals in the past two years. Ms. Ferguson also has extensive experience litigating complex, high-stakes tax cases at the Tax Court and federal district courts.
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Between State and Public: “What’s the Time in Vyborg?”, a Project by Liisa Roberts
by Olga Kopenkina (New York City) · Published 01/02/2004
Now living in Helsinki and St. Petersburg, Liisa Roberts was born in Paris in 1969 and received her BFA from the Rhode Island School of Design, USA. Since the early 1990s, Roberts has exhibited internationally, including group exhibitions at Artists Space, New York; Helsinki Kunsthalle and the Museum of Contemporary Art, Helsinki, Finland; The Museum of Modern Art, Oxford, England; P.S.1, Long Island City, NY; Bard College Center for Curatorial Studies, Annandale-on-Hudson, NY; and Bildmuseet Umeo, Sweden. Solo exhibitions have taken place at the Whitney Museum of American Art, New York and the Miami Art Museum, Miami, FL. She participated in the 1997 Documenta X in Germany and the 1999 Venice Biennale. Her work was featured in the Whitney Museum’s exhibit, The American Century in 2000, Museum of Contemporary Art Kiasma in Helsinki’s exhibit Faster Than Histor in 2004, and upcoming Whitney Biennale.
B.M. – Have you noticed, at this Manifesta, the rise of some new tendencies in European art?
I.B. – Maybe today we can speak about the objectification of art. Artists want to make artworks again. The thing that was important for the middle of the 90s, art activism, is today taking a back seat. Activism resists being recorded. What remains after it? Documentation? This is why today we can again see an interest in a work of art, an object. This certainly concerns video as well, of which there is plenty at the exhibition.
From the interview of Bogdan Mamonov with Iara Bubnova, curator of the Manifesta, International Biennale of arts in Frankfurt-on-Main, 2002. In: pH. #1. Kaliningrad, Center of Contemporary Art, 2003. P.41
The main challenge for me is to try to create a form in which a film or a document, for instance, is not a readymade frame into which one might fit a narrative or an image. Rather – in the process of creating its own image, and at each stage of its process – it is a potential framework for future action. This form would be one that is both happening and being documented at the same time.
Liisa Roberts. Artist questionnaire: 21 Responses: Roberts. In: October. MIT Press, Spring 2002. P.50.
“Disappearance of space” – perhaps this is how one can define psychological effect from art exhibitions in globalization era and what ultimately explains the major flaw of globalization that was insightfully characterized by Paul Virilio as the end of the engine era(This idea is expressed in the book: Paul Virilio. Speed and Politics. An Essay on Dromology. Foreign Agents Series. New York, Semiotext(e). 1986. P.40.).
Kim Levine, an art critic, formulated the similar phenomena as “power vacuum” in relation to the last Venice Biennale. The main consequence of this powerlessness and engineless is the absence of a point of return in the long circular races of art enterprises of a global scale. The big art project becomes that “floating machine” which gets rid of all signs of engine and simulates its own debris like a submarine which throws out false wreckages and fuel in order to flee from its chasers while anticipating its own disappearance.
Today many institutions of contemporary art that operate on the global level, including those of the famous international Biennales, can be compared to that strategic submarine which has no point of destination, their content and goal are motivated by the right to control an imaginary territory of contemporary art before their recurrent disappearance.
Indeed, who can now recall the particular reason why Venice became a site for the major event for the world art except of its role to be one of the main tourist attractions? And what the connections to local communities do the big institutions like Guggenheim in Bilbao, or Beacon Dia Center, recently opened in the depressed industrial town in the New York state, construct? Their localization is as arbitrary and inexplicable as a sudden tornado or alien spaceship descended in the empty field.
Researchers, navigators and passengers – curators, institutions, dealers and viewers – in search of unknown territories constantly face the trouble of inventions of new routes to realize absolute, infinite, circular voyages as their navigations do not presuppose any point of departure or destination but only mean symbolic exploration of the territory of contemporary art.
Inside of this situation, individual artists’ projects noticeably compensate the lack in articulate narratives of location and suggest their own models of project-institution producing such narratives and unfolding them in zones of conflicts, or places with ambiguous identity of borderline territory.
Moreover, the search for a location, which can at once suggest both the parameters and content for future projects, has became one of the most important tendencies of the current moment. It gets a distinct forms in the projects of net and media art which make a lot of efforts, while operating in the digital domain, to find virtual “zones” in the physical reality as well as the possibilities to use communication technologies for the purposes of describing and researching identities of the concrete territories.(For example, among the projects in the Eastern Europe, the Center for Information Culture was created in the abandoned space of the former military base in the Karosta, near to the city of Liepal, Lithuania (on the border between Lithuania, Belarus and Russia). In July 2003, the festival of net art took place there, during which artists explored the territory with the means of the net art.)
But that works of art that undertake this search within traditional visual arts and modes of exhibiting inevitably get under the fire of criticism which tends to accuse them in the absence of conventional representational models.
Last summer, I had a fortune to get involved in the events of the project initiated and directed by Finnish American artist Liisa Roberts. The project entitled “Vyborg: a Town Library in Viipuri” (2000) including the workshop “What’s the Time in Vyborg” (initiated in 2001) took place in the small Russian city of Vyborg, on the border of Finland and Russia.
Robert’s program for the summer events in Vyborg consisted of a series of performative (theatrical) tours around the city prepared by a group of teenagers (local residents and recent high school graduates). The tours were the climax of the long-lasting collaboration of Liisa and her colleagues with the young Vyborg residents to create a narrative scenario of Vyborg out of the discussions and actions, which Liisa had been initiating in the city for the past three years.
A main motivation for this project was, from the one hand, Robert’s desire to explore how the city of Vyborg, which several times, throughout its long history, underwent re-identification within the territories of Finland and Russia, and the last time – after its annexation by the USSR from Finland in 1944 – is perceived by its residents, and first of all, by its young generation; from another hand, how the individual perception of a place is different from the ideological canons and codes inscribed in city’s architecture, which in turn serves as a container for a “memory of nations.”
The task of Roberts’ team thus became the opposite to a museological image of the city: it was the research of the identity of Vyborg in its present time and creation of appropriate forms of its presentation. From the beginning, Roberts’ project implied far more than merely the tours around the city. It is a social experimentation of the artist who has always been engaged with the problems of perception, psycho-physiological and humanitarian aspects of image-making. Her early works have often taken the form of films that explore images in relation to the perception of viewers, often linkingreal-time with the time of representation by exploring possibilities of the production and projections of images.
These types of investigations have led Roberts to reflections of the time of a work of art, on the gap between artist’s idea of how work should function and its perception by public, on the pre-existence of images in the collective memory, and ultimately, on the narrative tendencies that form the present time of an art work.(One of the previous Liisa Roberts’ work, Sidewalk, is reviewed in: Okwui Enwezor, “Phases of Monument: Liisa Roberts’ Sidewalk” in Parkett 61, 2001. P.177-181.)
Therefore, according to Roberts’ initial plan, the result of the actions in Vyborg was to be a film as the best realization of her concept of the time of an artwork, which implied simultaneity of event and its fixation that a certain mode of filmmaking carries out.
However, immediately after the arrival in Vyborg in the end of 2000, Roberts, thinking of a possible visual project, immersed herself in the current debates on the new restoration plan of the public library built by Alvar Aalto in Vyborg in the 1930s as a manifestation of global modernism in the newly independent state of Finland.
The restoration of the library, which was during the Second World War deprived of all its functions and details of Aalto’s design, began in 1955 by the Soviet architects and continues until now under the auspices of The Finnish Committee for the Restoration of Viipuri Library (Viipuri is the Finnish name of the city).
Roberts stood for the inclusion of the Soviet period of the library history, which had been at the moment totally ignored by the Finnish restoration plan. Her argument was that the Soviet design of the 50s should have been reconsidered as an important stage in studies of Aalto’s library because the library is connected with the history of Vyborg as much (if not more) as to that of Western Modernism.
Such discussions became a form of Roberts’ participation in architectural symposiums and meetings organized by the Finnish Restoration Committee that is a rare example of artistic intervention in a zone between the state power and public sphere in discussions around the civil architecture in Russia.(For example, Liisa took part in the architectural seminar in Helsinki dedicated to the reconstruction of Aalto library in 2003; the discussion with one of the members of the Finnish Restoration Committee was a form of her participation in the exhibition “Fundamentalisms of New Order”, Sharlottenburg Center, Kopengagen, 2002. Roberts was invited to the seminar of critics, architects, and historians DOCOMOMO – Documentation of conservation of modernist buildings and urban projects – Vyborg, September, 2003.)
Besides her ongoing discussion with the Finnish architects, Roberts had directed for two years a creative writing workshop organized for Vyborg schoolchildren in the auditorium of Aalto’s library. For this workshop, she invited professionals from different fields such as journalists, architecture students, a poet, theatre director and artist to participate while collaborating very closely on its initial implementation with Olga Maslova, a psychologist from St.-Petersburg, and Edgaras Platelis, a young translator from Vilnius. Together this group improvised with the teenagers the creation of narrative scenario revealing their feelings and experiences in relation to the town.
The workshop’s location – the auditorium of Aalto’s library – was deliberately chosen: according to Aalto’s idea for the design of this room: its architecture, the undulated ceiling and large windows symbolized the democratic changes in the newly independent Finland. The undulated ceiling was designed for an even democratic sound throughout the space, while the large window provided a panoramic view of the main square of the city, bringing this live urban space into the archival time of the library.
At the inception of “What’s the Time in Vyborg?”, contemporary reconstruction was also beginning in this space. Children, when expressing their relation to Vyborg through writing in the workshops (in which Russian Poet Aleksey Parshikov, also played a catalytic important role) used the architecture of the auditorium as a point of departure in their reflections.(These essays are published on the website: www.auditorium.vbg.ru.)
Thus the collective reflections upon forms of time, in which the city exists, turned out to be a foundation for Roberts’ project, expanding her initial plan to make a film to the variety of actions in the city. Since then, the production of film was no longer considered as a forming process but became one of the project’s consequent parts.
Roberts virtually shifted in her work from discussion on forms of visualization to the stream of discussions, communication and live events, with not so much concern how aesthetically correct these events will suit to the conventions of the contemporary practice of installations and well-documented projects of art activism.
In other words, the issues raised by the work in Vyborg have little to do with the issues of visualizations although the actions provoked by Roberts are aimed at the semantic codes inscribed in city’s architecture and its aesthetic appearances. Rather, in her objectless and open-ended work, each event – organized by herself, children of Vyborg, or Finnish architects – became parts of the continuous narrative in which one action and its result provides a possibility for another.
One of the core moments of Robert’s intervention in architectural debates in Vyborg was a tour guided by Alexander Shver – one of the main figures who conducted the post-war Soviet restoration of Aalto’s library – for the Finnish Committee of the Restoration of Viipuri library.
Shver, who basically saved the most of original Aalto’s design in his restoration, told in details on his work in the 50s as well as on his memory about the library’s general appearance at the moment when he moved to Vyborg from Leningrad in 1957 and began to conduct the restoration. After this excursion significant changes occurred in the ideology of the Finnish architectural plan, having the Soviet period of Aalto library’s history included in the publication “PTAH” (a theoretical resource of the Alvar Aalto Academy).
The final achievement of this artistic intervention was an agreement between Roberts and the architects, which implied the removal of the stage built in the Soviet time in library’s auditorium that would allow freeing more space in the room designed “for public debates” for the variety of events like, for example, screening films.
Roberts’ work in Vyborg has an extraordinary ability to address within the time of the project different temporalities of a territory; these temporalities do overlap, but not necessarily coincide, with what we often understand by the present time of location. Here, it is necessary to focus on the understanding of time for which Roberts argues in her reflections on the currentidentity of Vyborg. This understanding obviously excludes the division into the present, past and future, but rather, applies the Deleuzian point about the fusion of “soft” form of the completed past with the “solid” of the current present.(Gilles Deleuze. Logic of Sense, chapter “The Porcelain and Volcano”.)
“Softness” can be seen in remembrance and nostalgia of the elder Finns for whom Vyborg is still a Finnish city Viipuri whose role as a cultural capital of independent Finland was formed between 1917 and 1939 – the time before the annexation, when the Modernist project of the Viipuri Library by Aalto came to symbolize the idea of national strengthened national identity in an international context.
In the contemporary context of Vyborg, this sentiment is no longer effective, nevertheless it does not cease to exist and is present in the collective memory of Finns, regularly undertaking their sentimental trip across the border to revisit their lost territory and the memories. For the Finnish consciousness (regardless of age), the past of Vyborg does not express distance and completeness, but rather it transfers to the present, which in turn plays a role of past here, expressing the withdrawal from all of the existential contents, and first of all, from the real existence of Vyborg itself. Indeed, Vyborg as an object disappears from those nostalgic discussions.
To the Russian “solid present”, Roberts’ work in Vyborg is important with its intention to take a location as a discursive space, which in the ideological and post-ideological reality of Russia was completely compromised, if not destroyed. From another hand, this is an attempt to localize discourse on time in parameters of one single territory and explore what makes geographical place to become a location in totality of all aspects of its historical past and present as well as people’s subjectivity. In other words, to return the discussions on time their object.
Actualization of the concept of location introduced by “What’s the Time in Vyborg?” is especially important today, when the idea of “global city” gets compromised as it annuls different levels and forms of collective consciousness and memory within one single global narrative.
A value of separate territories in this narrative is reduced to a price defined by their ratings on global market and established in accordance to fetishized geography of the commercial projects as well as ruling ideologies. In Russia, one of such projects was a celebration of the 300-anniversary of St. Petersburg (not accidentally, the events in Vyborg organized by Roberts coincided with the last summer festivities in St. Petersburg as well as with festivities of Vyborg’s 600 years celebrations), which revealed a blatant incongruity of the state imperial attitude with the actual feelings of St. Petersburg residents who mostly chose to temporally migrate to the countryside during the major city’s events.
Hence, post-Soviet contempt for historicity of places, in Vyborg expressed through a complete abandonment of the unique medieval city’s center and most of its old streets and courtyards, from one hand, and Finnish nostalgia, from another – in a dialogue with these two parallel, constantly overlapping forms of consciousness Roberts realizes her “search” of the present time and a vector which will eventually lead to recognition of the future.
The goal imposed by Liisa Roberts and her young collaborators (Dina Grigorieva, Yana Klichuk, Liuba Mukhorova, Yulia Popova, Olga Fedotova, and Ania Yaskina) in their tours was to make – with the help of the characters created in the writing workshop in whose roles the girls decided to explore the city – connections between the different codes and time zones, previously unrecognized in city’s landscape.
At first glance, the girls’ performances in Vyborg recalled Situationist projects of the late 50s, with their focus on performance as a way to get an actual experience in a city. But the tours in Vyborg are different from their Situationist predecessors, far from the intention to construct “situations” – a sort of universal formulas of behavior meant to help to recognize the models of the future social life – as well as the practice of “drift, ” the route of which was oriented to the jungles of a standard industrial city.
To the Situationist belief in a general formula to be used in the creation of any location by request, young Vyborg guides preferred the subjectivity of those who are involved in game, and focus on the history and peculiarities of the city’s mythology.
Roberts’ project does not leave any doubts in consistency of her exploration of the new genre which can hardly be defined in terms of a visual project, but rather as building a parallel reality – disruptive, interpretational, playful – which unfolds as a permanent exchange and dialogue within (and with) the existing one.
Nevertheless, Liisa Roberts has been invited to participate in a number of international exhibitions and one of them is “Faster than History” which will be open in the museum Kiasma – Museum of Contemporary Art, Helsinki, in January 2004. A transfer of Vyborg project to the representational context of an exhibition (whose focus is on the myth of “fast development” with its acceleration of the concept of future in discussions about social history of so-called “peripheral” zones of Europe in the last 15 years) – undoubtedly an experiment which will create a possibility to continue those debates and the process of manufacturing of the counter-image of Vyborg on the Finnish territory, in close juxtaposition of its “real” time with the imagined one, carried by the Finnish consciousness.
The success of this project in Finland will definitely depend on the way how Finnish organizers understand that the debates around the question “What’s the Time in Vyborg?” lie in the dialectics of time of individual territory and common history (in the case of Vyborg, it is determined by two important events – building of Aalto’s Viipuri library and post-war annexation of Vyborg by the USSR) – and how the archiving and documenting of the present in this dialectics constitute an event of the project.
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Cloudy With A Chance Of Meatballs/ dir. Phil Lord & Chris Miller/ 2009
A cooky inventor creates a machine that turns water into food. The machine ends up in the sky somehow, and it rains down food…
Did you just roll your eyes? I know I did when I first heard the silly premise of Cloudy With A Chance of Meatballs. And yes, it IS a silly premise. Loosely based on the 1978 book of the same name, the directors, writers, animators, etc. obviously had fun with this premise of food falling from the sky, as there was little bits of slapstick all over the place, sometimes too much, and many times, WAAY overdone. However, a silly premise does not necessarily mean bad movie. In fact, underneath all the comedic bits, overacting, food falling from the sky, and outrageous action scenes lies a pretty decent animated film. Actually Cloudy With A Chance of Meatballs is more than decent, with subtle sophisticated social commentaries, a fun supporting cast, a genuine telling of a strained relationship of a father and son, it’s a really deep and engaging movie.
Cloudy tells the story of wannabe inventor Flint Lockwood, and his invention to save the small island port town of Swallow Falls. Of course, the machine turns water into food, and food rains down into the town. At first, everybody is happy, but then, (as always), something goes wrong and Flint and company need to fix it. As stated before, its not so much the story that makes the film, its the depth that the directors, writers, animators, etc. placed in not only the personalities of all the characters, but also the intricate dialogue and situations said characters were placed in that truly makes this film engrossing. True, with such an outrageous plot, there are many elements that just do not work. For one, there really is never a credible villain, like stated before, the mounds of food eventually gets tiresome, and the final act of the film just disintegrates into an action packed food mess. But all those negatives go by the wayside once you hear the hilarious voice acting of Mr. T as the town’s only cop.
I was also a fan of the animation. Distinct features were great for the character designs, i.e Tim Lockwood’s bushy unibrow, and the characters had a muppet/ cg vibe that just worked. The animators did a great job not only with the action scenes (some which were overdone), but also in those subtle touching moments of drama and reflection.
There are many animated films that have silly premises (like an old man tying a bunch of balloons to his house so that he can fly to South America) that for some reason I can take dead serious. And many other times, I can spot a cornball, slapstick animated movie coming in the distance. Cloudy With A Chance of Meatballs seemed like that cornball animated flick based on its trailer:
Just give it a chance, it’s okay to be silly and maybe just like its protagonist, you will see something more than what is initially seen.
Posted in Film, Reviews, Video
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Indian sham election in IOK mere military exercise: JKFM
May 2, 2019 | General, Official News | Share:
Jammu, May 02, 2019 (PPI-OT): In occupied Kashmir, the Chairman of Jammu and Kashmir Freedom Movement (JKFM), Muhammad Sharif Sartaj has said that the sham Indian parliamentary election is nothing but a military exercise and in no way can be alternative to Kashmiris’ right to self-determination.
Muhammad Sharif Sartaj in a statement issued in Jammu said that like past, the people of Kashmir rejected the recent farcical elections by staying away from the poll process. He said Kashmiris gave a clear message to India and the rest of the world that they have no interest the so-called elections but wanted only their right to self-determination.
Muhammad Sharif Sartaj said the people of Kashmir have given unprecedented sacrifices for getting freedom from India’s forces occupation over Kashmir and not for the fraud elections. He said the sacrifices of Kashmiri people would not be allowed go waste and one day India would free Kashmir.
He also prayed for Kashmiri martyrs and quick recovery of the health of APHC Chairman, Syed Ali Gilani. Meanwhile, a meeting held in Kashwan area of Kashtwar with Imam Markazi Jamia Masjid, Molvi Tariq Hussain in chair praised the formation of ‘Jammu and Kashmir Youth Forum’ in Jammu region.
The participants of the meeting expressed the hope that the youth of the region would fulfill their responsibilities and decided to provide full cooperation to the youth forum. The meeting also discussed the problems of Chenab Valley and prayed for the health of APHC Chairman, Syed Ali Gilani.
Maulana Ghulam Muhammad Rizvi, Haji Abdul Majeed, Gul Muhammad, Molvi Muhammad Ashraf, Molvi Manzoor, Molvi Ghulam Qadar, Molvi Muhammad Iqbal, Molvi Bashir Ahmad, Hafiz Tajuddin and others participated in the meeting.
Kashmir Media Service
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Category: General, Official News
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Pakistan urges UN Security Council to address Kashmir, Palestine disputes »
Islamabad, January 16, 2020 (PPI-OT): The Resident and Humanitarian coordinator, Mr. Knut Ostby and the United Nations Country Team in Pakistan are deeply saddened over the loss of precious lives resulting from the heavy snow and rainfall in Baluchistan and…
Srinagar, January 16, 2020 (PPI-OT): In occupied Kashmir, former puppet chief minister, Omar Abdullah, will be shifted to a house near his official residence. Omar Abdullah was taken into custody after Modi-led Indian government abrogated special status of Kashmir and…
Lahore, January 16, 2020 (PPI-OT): The position of the river inflows and outflows at Tarbela, Mangla and Chashma along with the reservoirs levels and the barrages today is as under: Rivers: Indus at Tarbela: Inflows 17700 cusecs and Outflows 17700…
New Delhi, January 16, 2020 (PPI-OT): India is planning to cut some imports from Turkey and widen curbs on palm oil from Malaysia to oil, gas and other products. The two Muslim countries are being targeted for their criticism on…
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Partnership with the Edmond de Rothschild Group
Investment Vehicles
Amethis Finance increases its stake in CIEL Finance Limited to 24.9%
Amethis Finance, which already acquired in February 2015 a 17.1 % participation in CIEL Finance Limited, the banking and financial services cluster of the Mauritian group CIEL, has increased its stake by 7.8%, as initially planned, thus confirming its trust and long-term commitment towards CIEL Finance, in which it now holds a 24.9 % stake.
This second transaction – which will allow CIEL Finance to complete the acquisition of CIEL’s interests in BNI Madagascar – is in line with the strategy of Amethis Finance and CIEL Finance to further consolidate their partnership in order to expand their footprint in the Sub Saharan Africa region and the Indian Ocean. Both companies aim at capturing further opportunities in the financial industry in the above mentioned emerging regions, with a huge potential particularly in banking & financial services. Amethis and CIEL Finance expect to leverage on their shared field of expertise and best practices as well as their deep knowledge of the African market to generate additional business openings, either through acquisitions or organic growth related to the financial industry.
“We are delighted to have engaged in a long term partnership with Amethis Finance, which has an extensive experience of the banking and financial industry in Africa through long-term investment in leading African companies. This second part of the transaction will give us more firepower to further expand our footprint in the Sub-Saharan region and the Indian Ocean”, said Marc-Emmanuel Vives, CEO of CIEL Finance.
For Laureen Kouassi-Olsson, Financial Institutions Head at Amethis Finance, “Amethis is pleased to confirm its support to CIEL Finance Limited’s ambition to become a regional offshore and onshore financial platform.”
A propos de CIEL Finance Limited
CIEL Finance Limited (“CFL”) is a subsidiary of CIEL Limited (“CIEL”) and the specialised Banking & Financial Services cluster of the group, today actively involved in 4 sub-sectors of the financial industry:
Banking (Bank One / BNI Madagascar),
Fiduciary Services and Companies / Funds Administration (MITCO),
Asset Management (IPRO), and
Private Equity (Kibo).
CFL’s mission is to develop a wider and coherent presence in Sub-Saharan Africa and the Indian Ocean, where we see a huge growth potential for the financial industry in all its components, based mostly on the rapid economic development of the region. It is also aiming at generating additional value thanks to fostering synergies between the units of CFL group, and with the partners associated to the group at various levels.
About Amethis Finance
Amethis Finance is an investment vehicle dedicated to Africa, with a total investment capacity of USD 530 million. Amethis Finance has been created by a team of experienced investors and bankers led by Luc Rigouzzo and Laurent Demey and by La Compagnie Benjamin de Rothschild, subsidiary of the Edmond de Rothschild Group. They have been joined by a large group of private investors combining financial institutions and family offices. Amethis Finance is a “one stop shop” which provides all long-term financial instruments (long-term debt, equity and quasi equity investment), with high standards and objectives in terms of development, social and governance criteria. Amethis Finance ambitions to tap into a significant potential offered by the financial institutions landscape in Sub-saharan Africa and to dedicate 40% of its activity to this industry.
About CIEL
CIEL Limited is a leading diversified investment company in Mauritius, operating five business clusters spread across Mauritius, Africa and Asia with 27,000 employees. Since its beginnings in agriculture in 1912, CIEL is continuously exploring new avenues of development and international expansion. In January 2014, CIEL was listed on the Official Market of the Stock Exchange of Mauritius (ticker symbol: “CIEL.N0000”), following the merger of one of its investment companies into the Group’s holding company. As at 31 March 2015, its portfolio was valued at 13.7 billion Mauritian rupees (USD 386 M). CIEL is one of the largest listed Mauritian companies with a market capitalisation as at 31 March 2015 was 10.5 billionMauritian rupees.
For more information, visit www.cielgroup.com
Amethis Finance (www.amethisfinance.com)
Laureen Kouassi-Olsson (Financial Institutions Head):
Mail : laureen.kouasis-olsson@amethisfinance.com
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Amelie Audibert (HR and Communication Manager)
Mail : aaudibert@cielgroup.com
Luc Rigouzzo in Option Finance
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Merec : Africa Food Deal of the Year
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Amethis has participated to Ambition Africa
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Amsterdam Times
Home Fun Kevin Spacey: Scotland Yard investigates third sexual assault allegation
Kevin Spacey: Scotland Yard investigates third sexual assault allegation
Police are investigating a new allegation of sexual assault against Kevin Spacey.
Scotland Yard received the claim on 13 December. It alleges that a man was assaulted by the Oscar-winning actor in Westminster, London, in 2005.
The police force did not name Spacey but said the alleged perpetrator is the same person who was the subject of two earlier complaints.
Those are alleged to have taken place in Lambeth in 2005 and 2008.
A Scotland Yard spokesman said: "On 1 November, City of London Police referred an allegation of sexual assault to the Metropolitan Police Service.
"It is alleged a man assaulted another man (victim one) in 2008 in Lambeth. On 17 November we received allegations that the same man sexually assaulted a man (victim two) in 2005 in Lambeth.
"On 13 December we received an allegation that the man sexually assaulted a man (victim three) in 2005 in Westminster."
Spacey, 58, has won two Oscars – best actor for American Beauty in 2000 and best supporting actor for The Usual Suspects in 1996 – and was artistic director of The Old Vic theatre in London between 2004 and 2015.
Spacey has been accused of sexual assault and harassment by a number of men and, according to his spokesperson, is "taking the time necessary to seek evaluation and treatment".
The first allegation was made in October by Anthony Rapp, who said Spacey made advances towards him when he was 14 and Spacey was 26. Spacey claimed to have no memory of the events and has issued an "absolute" denial of the other allegations that later emerged.
He has since been dropped from Netflix series House of Cards and was replaced by Christopher Plummer in Sir Ridley Scott's film All the Money in the World.
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Facebook Insights — “Viral” Measures and EdgeRank
Home ≫ Blog ≫ Social Media ≫ Facebook Insights — “Viral” Measures and EdgeRank
In my last post, I provided an update as to how to interpret the primary measures and dimensions (organic/paid/viral) that are available in the latest iteration of Facebook Insights. While digging into those dimensions, my fellow Resource Interactive analyst, Mike Amer, stumbled across some mild unpleasantries that don’t quite square with how Facebook talks about brand pages in their formal documentation.
On the one hand, Facebook would have us thinking that it’s all about virality. That’s one of the reasons they’ve made “Friends of Fans” such a prominent (if laughable) metric!
To recap, the viral reach of a page or a post is the number of unique people who were exposed to content as a result of another user generating a story (“talking about” the page or post – liking, sharing, commenting, etc.). This differs from organic reach, which is the number of unique people who visited the page or saw an item in their news feed or ticker as a direct result of the page posting the content.
Here are a couple of dirty little clarifications and secrets about virality, though:
The most common type of viral reach is from someone liking your page – despite Facebook’s insinuations that getting people to like and comment on your page posts will tap into that ginormous “friends of fans” number…those user actions tend to go nowhere. When someone likes your page, though, that generates a story that has a meaningful viral reach (unfortunately, that is a one-time viral exposure — that same user may comment on 10 page posts over the next week and the viral reach generated from those actions will be virtually nil).
A page’s virality is dramatically impacted by paid media – If a Facebook Ad for the page is run and a user is exposed to the ad, then that exposure counts as 1 person towards the page’s Paid Reach. If the person clicks the Like button, Facebook will record that as a Like Source of “ads” (why they don’t have that data field name capitalized bothers my OCD, FWIW). But, a good chunk of their friends are going to get an item in their ticker that the person liked the page. All of those friends being exposed get counted as viral reach and impressions.
Oh…yeah…and Facebook Questions – Facebook Questions are the single type of Facebook page post that appear to drive meaningful viral reach (presumably, because the Ask friends action is more valued by Facebook than other actions such as standard likes, comments, and shares). Questions are good for that! Unfortunately, we’ve seen several cases over the last month across different pages where the Organic Reach of Facebook Questions was reported as dramatically lower than the typical reach for a status update on the page. It’s unclear whether those lower numbers reflect reality or whether they are simply a Facebook Insights glitch
All this is to say that viral reach is messy (…and don’t take what Facebook espouses at face value).
In my last post in this unofficial series, I’ll provide a list of the KPIs we’ve been gravitating towards with our clients and why.
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Home News HMD Global’s “first smartphone with PureDisplay screen tech” starts selling in Kenya
HMD Global’s “first smartphone with PureDisplay screen tech” starts selling in Kenya
Emmanuel ChenzeNovember 7, 2018101.4k
So far, we’ve already seen HMD Global release into the Kenyan market the Nokia 2.1, Nokia 3.1, Nokia 5.1 and, recently, the Nokia 6.1 Plus. As such, it is only logical that the Nokia 7.1 (give or take the Plus model) follows suit since it is already available in the global market, right?
Starting yesterday (November 6th, 2018), the Nokia 7.1, which was only announced globally last month, is available across the country through select retailers.
The device’s cling to fame, besides being the second Nokia-branded device from HMD Global to launch in the country with a feature some of us love to hate, the notch, also happens to be the first such device from the Finnish company that arrives packing its “PureDisplay screen technology”.
Marketing speak aside, what that means is that the device’s 5.84-inch display provides its users with the best in-class HDR10 experience (I have tried to explain what HDR here so maybe you may want to have a look at that before proceeding). What this means is that the display has a higher contrast and clarity level thus allowing light and dark areas to pop. This is useful for similarly-tailored content that users can access from YouTube, Netflix and such. What’s more, the device will even convert standard definition content to HDR level before beaming it, in real time.
Like other Nokia devices we have seen released this year, the Nokia 7.1 is an Android One smartphone and we all know what that means, don’t we?
Of course, it’s not a Nokia if the photography isn’t great, right? HMD Global will be crossing its fingers that the ZEISS optics which make it into the device, like the Nokias from a decade ago, go a long way in helping its devices maintain an edge over rivals like Huawei, Oppo and others who have introduced very attractive camera-centred devices in the Kenyan market this year.
READ: Huawei Y9 2019 now comes in a special limited edition "Purple Effect" colour
Like the two aforementioned Chinese device makers and its other competitors, HMD Global has also incorporated AI (Artificial Intelligence)-driven features to make the Nokia 7.1 smarter, faster and highly adaptive of the usage situations it is likely to find itself in, complementing features like Adaptive Battery arriving at the operating system level courtesy of Android 9 Pie. The AI smarts also, naturally, extend to the cameras. The device’s front-facing camera harnesses the power of AI to create “animated 3D personas/masks and filters”.
Specifications of the device are as follows:
Size (minus the camera bump) and weight: 149.7 x 71.18 x 7.99mm, 160g
Display: 5.84-inch PureDisplay Full-HD+ protected by Gorilla Glass 3
Camera: Main 12 MP + 5 MP; Secondary 8 MP
Processor: Snapdragon 636
Memory: 4GB RAM; 32 or 64 GB internal storage (expandable up to 400GB)
Operating System: Android 8.1, Oreo
Battery: 3,060mAh
Network: 3G, 4G
Connectivity: Wi-Fi 802.11 a/b/g/n/ac, Bluetooth 5.0, USB Type-C
Others: Dual-SIM
The Nokia 7.1 is available in Gloss Midnight Blue and Gloss Steel colours for Kshs 30,000, a little less than the equivalent pricing in other markets.
Nokia 7.1 price in Kenya
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Emmanuel Chenze
Have something that you believe I need to have a look at? Hit me up: echenze [at] androidkenya.com
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Tag Archives: werewolves
June 3, 2016 by Tina Williams
**REVIEW** ~ Angelis Vampire Series, by Shane North
Paranormal/Fantasy Romance
If you are after a romantic paranormal/fantasy read which has plenty of action with a kick-ass heroine or two, out -of-this-world lovemaking scenes, magic and mayhem, then you will want to consider Shane North’s Angelis Vampire series. Aside from the vamps there are werewolves and a host of other immortal beings who are striving to co-exist alongside the world of mortals. And, talking of worlds, we also have the key role played by Angelis, a world in another time dimension but which plays a pivotal role in the series.
If you want to read an interview with Shane, posted previously on our blog, which includes an extract from Shannon, the first book in the series click here. You can currently download Shannon for FREE:
Amazon US Amazon UK
Shannon’s life is happy except for her nightmares, but when she watches her mom and dad being murdered by the monsters in her dreams, her life falls apart. Her best friend turns out to be a werewolf, the man she thinks of as her other father is the alpha male, and her long lost uncle is a vampire lord from Angelis. Angelis is in another time dimension, a world ruled by Royals, a pureblooded line of vampires with powers never seen in this time dimension. Angelis is a medieval world of castles, and ancient magic that her mother and uncle were forced to leave to save their lives.
Shannon’s journey leads her to follow her destiny and meet the love of her life. Destiny and her uncle lead her to find out what she really is, where she came from, and to become the strongest immortal to live. Shannon learns to kill quickly, and to love like there’s no tomorrow when she meets her mate from her dreams. Simon, an eight-hundred year old Viking has searched the world for his true love when he meets Shannon. What will Shannon’s uncle, Simon’s maker, have to say about this? A young woman from South beach, destined to overthrow the vampire council and rule the immortal race with the help of the ancient Shaman Neeb.
Paranormal/Fantasy Romance with a powerful heroine ~ 4 stars
Shannon, book #1 in the Angelis Vampire series is a sweet, but at the same time erotic paranormal/fantasy romance, with an original storyline. It contains a powerful heroine, magic, vampires, werewolves, fated mates and a battle between good and evil.
For me the read also has the feel of a New Adult/coming of age novel and this fits the storyline as the kick-ass heroine Shannon is trying to come to terms with her legacy after being thrust into the world of immortals. Her life is now far more complicated than that of a young woman from South Beach! She finds out that she is descended from a union between Callidora, a royal from Angelis, a world in another time dimension, and Connor an alpha werewolf.
Instead of going clubbing and shopping she needs to concentrate on using her growing powers – which due to her lineage are considerable, to destroy the evil Vampire Assembly, who murdered he parents and seize power. To the Assembly Shannon, the offspring of a forbidden union of werewolf and vampire, is an abomination to be destroyed.
Shannon’s task is not easy – she has to come to terms with the vast changes that are taking place in her life and the physical and mental challenges of being an immortal. It is fortunate that she has found the vampire Simon, her life-mate.
There are a numerous battle scenes, where Shannon and others show their combat prowess and also some scorching lovemaking scenes. The novel contains a number of engaging characters: her powerful uncle Damon, also from Angelis, who exudes charm, strength and humour; her best friend Cait, a werewolf and Cait’s father Keegan and of course her very own Simon, who is a girl’s dream.
I enjoyed the read and the author and the series has a lot of promise.
Please note, a copy of the novel was given to me by the author for the purpose of a fair and honest review.
My name is Shannon O’Callaghan and I’m immortal. I live in an amazing world of time travel and magic, where vampires and werewolves are normal and I call them family A family some would say are monsters, but they love me unconditionally and it’s the life I was meant to live. My father was Connor O’Callaghan, a visionary that led the wolves to peace and prosperity. My mother was Callidora Angelis, a Royal vampire from another time dimension. Their love and life together are what made my life possible, but, it is also what caused their death. And, it’s their death that fuels my journey of revenge on those who stole my life.
This immortal word is controlled by The Vampire Assembly. The Assembly is an evil group of twelve who decides the fate of its followers. They are devils dressed like mortal men who kill with pleasure and live off of blood slaves they keep in their dungeons. They are evil, they are responsible for my parents’ death, and I will see them dead. My day for revenge is finally coming and The Assembly is mine to kill. Then and only then will I rule this land as their queen.
Sexy and Fast-Paced! ~ 4 stars
The pace and the action hot up in Shannon’s Revenge, book #2 in the Angelis Vampire series. Shannon is now coming to terms with her considerable powers and, despite a few minor hiccups, she is starting to show great promise as a warrior and future ruler. Uncle Damon and Shaman Neeb, not to mention Cait her best friend and life-mate Simon are all on hand to support her through the process.
It is only a matter of time before Shannon, supported by an alliance of vampires, werewolves and the Elvin race, goes head to head with the Vampire Assembly and its leader x. Before this happens Shannon needs to bide her time, hone her growing powers and magic strike when the time is right. Yet the council leader Antonious is no fool and Shannon and her supporters will need all their wits about them.
I enjoyed the Shannon’s growth and character development in this novel and also how the author developed the other characters, especially Uncle Damon, with whom she has many verbal sparring matches. I loved the sexy scenes between Shannon and Simon, the humour and also the many action scene. Shannon is a powerful role model and heroine for although she has a soft heart she is a powerful immortal and is no one’s fool. She does not hesitate to do what is necessary and is dedicated to her goal of annihilating the Vampire Assembly. The ending is a worthy one.
Recommended for lovers of paranormal/fantasy romance who like an erotic read and a strong heroine.
Death has arrived in earth’s time dimension. A foul stench filled Shannon’s nose, a smell of sulfur and death. This might have been a vision, but her power spiked as she sensed the source and moved towards it. Her life force surrounded her as her swords appeared in her hands. She gripped them tightly and stepped through a massive oak door. Before her stood a giant of a man.
His essence was black as coal, and his soul had long been lost to his dark side. His ancient leather armor looked old and battled; it smelled musty from the dried blood and looked dry and brittle. This had to be Kyran. Evil always had a dirty, unkempt appearance, and his aura was encircled with death. She could sense his blood was similar to Damon’s, and she knew she would take great pleasure in killing him someday. But what happens when Kyran is taken to earth’s time dimension by Neeb’s evil brother, seeking to kill the remaining royal Angelian family and end their bloodline forever.
In this riveting spin off from Shane North’s Angelis Vampire Series, an unknown Angelian is faced with death, her new life and the destiny the fates have planned for her.
High Octane and Entertaining! ~ 4 stars
Reagan’s Destiny is both a spin off and a continuation of the story arc contained in the previous novels in the series, Shannon and Shannon’s Revenge. The Vampire Council having been dealt with, the threat in this novel comes from Angelis no less, the medieval and magical world where Shannon’s mother and uncle were compelled to leave. Evil in the form of Kyran stalks Shannon and her uncle Damon, intent on destroying what remains of the royal Angelian family.
Reagan, a young woman with Angelian blood plays a key role in this battle and I enjoyed how this novel focused on her story, whilst including the characters I have grown to love from earlier novels. Shannon and Cait are destined to forge a strong relationship with this headstrong individual, but the path to their burgeoning friendship is not plain sailing. We know from Shannon’s trials that adapting to a life of an immortal and facing up to one’s destiny is not always easy and the author does a god job of exploring these issues, whilst maintaining a high octane and entertaining read.
Reagan is fortunate in that she manages to find unexpected love in the form of the vampire Lucius who she finds is her life mate. There are plenty of hot, sweet and romantic interludes amongst the bloody battle scenes and magic and I enjoyed the contrasting scenes. Kyran, as a powerful Angelian, is a well drawn and formidable enemy. Aided by the brother of Shaman Neeb, it will take everything Reagan, Shannon and Damon have in their arsenal to bring about his downfall.
Recommended to fans of paranormal/fantasy romance.
Amazon UK Amazon US
Posted in Paranormal, Review, REVIEWS (ALL) - Reverse Chronological Order, Romance
Tagged erotic-romance, fantasy-romance, paranormal-romance, reagan's-destiny, shane-north, shannon, shannon's-revenge, shannon-angelis-vampire-series, the-angelis-vampire-series, vampires, werewolves
April 27, 2016 by Caroline Barker
**Review** Vampires of Maze (Beautiful Immortals series 2, book 3) by Tim O’Rourke
She’s back! Wicce Julia is hoping to bring peace to the Beautiful Immortals as the werewolves and vampires are at war with each other. But, do both sides really want to negotiate? It appears not. After travelling with weres to find the vampires, it cannot be helped that by spending time with them she is starting to find friends among them. And, as it is the weres who appear in more danger, the reader won’t help but side with them during the beginning of this series. With chases, fights, romance, mystery and magic this is a must-read for any paranormal/horror fan!
Title: Vampires of Maze (Part Three) (Beautiful Immortals, series 2)
Author: Tim O’Rourke
Genre: Paranormal thriller/adventure/romance
Blurb: From Tim O’Rourke #1 bestselling author of ‘Werewolves of Shade’ (Beautiful Immortals Series One) comes ‘Vampires of Maze’ (Beautiful Immortals Series Two) a vampire and werewolf romance with a twist.
Witch, Julia Miller, has been sent by the Wicce to bring an end to the war that rages between the Beautiful Immortals. Joining a pack of werewolves, Julia must travel with them to a land unknown to her. Here she will learn the horrifying truth about the dark secrets hidden in the town of Maze.
To stay alive, Julia will not only have to figure out who to trust but also who to love. For Julia’s worst nightmares are about to get a whole lot more terrifying as she heads into the war raging between the vampires and werewolves where even her own magic abilities won’t be able to protect her.
Note: This ends on an unbearable cliff-hanger. Part Four will be published within the next few weeks.
The story picks up exactly where we left off in Vampires of Maze part 2 within it’s first sentence. That terrifying cliff-hanger from book 2 is answered immediately. However, there is no time for calm as soon afterwards Julia and her were-friends are being chased down by many vampires. This is a fantastic action sequence with the speed of the chase and bullets being fired all over the place.
Julia was hoping to negotiate between the wolves and vampires to bring peace and stop the war between the two Beautiful Immortals. However, Julia’s thoughts begin to change as she realises that the vampires do not seem willing.
“And as the vampires looked through the air at us, faces twisted with hate and claws scratching the walls… any ideas I might have of ever finding peace with these creatures seemed impossible.”
We are clearly reminded of previous scenes from earlier on in the story via great dialog. In this instalment we discover what Julia’s nightmares entail, and why she can’t let herself become too close to a Beautiful Immortal.
I love Morten’s character: an older were that has guided them to where the vampires are at Maze. He has stayed in their company and worked with them, but he has appeared quite fragile until now. His courage and loyalty shows greatly in this instalment.
“… with an agility and speed that defied his decrepit look, Morten once more sprang into the air.”
Werewolves Trent and Calix come across as quite protective of Julia. They support many of her ideas, and even calm Rhea as her jealousy and suspicions of Julia and Trent burn more ferociously. I do believe that they Trent and Calix are taken with Julia and like her in an intimate way, however she also may be the answer they need as they begin to realise the wicce powers she possesses.
With every story I read of Tim O’Rourke‘s I feel I am taken as far as my threshold will go in terms of terror, suspense, thrills, passion and emotion; and yet there is always more with surprises and shocks, and even gentle, tender moments from some of the tougher characters when you least expect them.
The author writes so clearly and straightforward, with great description that you escape in the story and become a part of it. A rare quality that fans of the author embrace easily. Book 4 of Vampires of Maze is due for release in early May.
A copy of Vampires of Maze part 3 was provided by the author in return for a fair and honest review.
Vampires of Maze part 3 is available at Amazon UK and Amazon US.
You can catch up with all info and reviews for the Beautiful Immortal Series 1, Werewolves of Shade, and the previous books of Series 2, Vampires of Maze below:-
Werewolves of Shade (Beautiful Immortals #1) – short story
Vampires of Maze (Beautiful Immortals series 2 #1) – short story
Vampires of Maze (Beautiful Immortals series 2, #2) – short story
Posted in Horror, Mystery, New Adult, Paranormal, Review, REVIEWS (ALL) - Reverse Chronological Order
Tagged Beautiful Immortals series 2, book review, horror, mystery, paranormal, short story, Tim O'Rourke, vampires, vampires of maze part 3, werewolves
March 31, 2016 by Caroline Barker
**Review & 2x Signed Giveaway** Vampires of Maze (Beautiful Immortals series 2, book 2) by Tim O’Rourke
The Beautiful Immortals series 2 is continued with the second instalment of Vampires of Maze. The war between the vamps and weres has been well under way, and it appears that there are few shifters left. Wicce, Julia, travels to England with a small group of weres in the hope of negotiating with the vampires to keep all parties, including humans, alive. But, is it possible to negotiate with such beings? Is she experienced enough? And, what of her personal feelings to the weres around her? She can only keep her distance to a certain degree from those she travels with. As tension runs high, and action is inevitable, you’ll be holding onto your seats with this paranormal thriller series from the talented Tim O’Rourke.
Please scroll down for a chance to WIN a SIGNED COPY of Vampires of Maze part 1 🙂
Title: Vampires of Maze (Part Two) (Beautiful Immortals, series 2)
Release date: March 12th, 2016
Note: This ends on an unbearable cliff-hanger. Part Three will be published within the next few weeks.
Vampires of Maze creates so much suspense and tension that the reader is glued to their seat. Tie that in with the action and gore, and the reader becomes easily addicted, awaiting the next instalment just as many viewers feel towards The Walking Dead (tv series). And, like the tv series, the Beautiful Immortal series leaves you each time on a terrifying cliff-hanger.
As a fan of O’Rourke’s work, I am quite prepared for the cliff-hangers, knowing that I will be in suspense until the next instalment, and knowing that they are going to be truly great. And, although they are all usually very surprising and horrifying at times, nothing quite prepared me for the SHOCK I was to find at the end of this particular episode! It’s written fantastically, but will leave you quite gob-smacked (although I am hoping for a different outcome than the one suggested). It’s a great thing we won’t have to wait too long before the next instalment is to be released!
Julia, the Wicce, and the small group of werewolves that she has travelled with are bound for where they believe the vampires are in the village of Maze. Although, they both have differing plans on how to end the war between the vampires and wolves; the weres are ready to attack and fight to the vampires death it seems, whereas Julia is hoping to negotiate, thus saving everyone including humans. Is she really that naïve to think the vampires would even listen? Or, can she stun them enough, using her magic, and then speak with them?
Julia is mocked and given her fair share of sarcastic comments, especially coming from were Rea. There has already been tension between the two, and this escalates when Julia is found in Trent’s arms after waking from a terrible nightmare. Although an innocent situation, Rea doesn’t exactly see it this way, and it is clear that Rea has deep feelings for her old lover. Will Rea be an enemy of Julia’s or can they reconcile their differences?
The were character, Calix, is growing on me more and more. Yes, he opens his mouth, he’s sarcastic and he likes a cheeky feel of Julia every now and then, but there is still a feeling that he has Julia’s back and sometimes has a kind word to say for her, even if he’s unsure of her Wicce ways. In my last review of Vampires of Maze part 1 I likened him to the character of Ajax in the 1970’s cult movie The Warriors, and I still felt the same way in this instalment. My favourite of Tim’s male characters is were Harry Turner from the time-travel paranormal Samantha Carter series, but Calix is great competition for first place.
This short story builds up suspense and is not without some fast-paced action, horror and gore. It’s terrifyingly exciting, full of mystery and holds a great deal of atmosphere. You’ll feel a part of the team with Julia and the shifters, and you won’t want to leave it there. I cannot wait for the next part of their journey!
GIVEAWAY!!!
The author, Tim O’Rourke, has 2 signed paperbacks of Vampires of Maze part 1 up for grabs!!!
For a chance to win one of two paperback copies all you have to do is add your name in the comments list below (or on our Facebook page) before Friday 8th April 2016, when the two lucky winners will be randomly selected. (We’d also appreciate a ‘share’ or retweet where possible.)
Good luck, guys
Vampires of Maze (Beautiful Immortals series 2 #1 – short story
Posted in Competition, Giveaway, Horror, Mystery, New Adult, Paranormal, Review, REVIEWS (ALL) - Reverse Chronological Order
Tagged Beaautiful Immortals series 2, book review, Giveaway, horror, mystery, paranormal, short story, signed giveaway, signed paperback, Tim O'Rourke, vampires, Vampires of Maze part 2, werewolves
June 17, 2015 by Caroline Barker
**REVIEW** Werewolves of Shade (Beautiful Immortals #6) by Tim O’Rourke
Tim O’Rourke’s Werewolves of Shade (Beautiful Immortals series 1, books 1-6) has been such a brilliant read. With one book being released each month, Tim has surely kept us all on our toes with some fantastic cliff hangers. Now the last book of the first series is available, and so for those that haven’t read this series yet, this is the perfect opportunity for you to read all six books in one go, and I will warn you now – you won’t be able to put these down for a second!
Title: Werewolves of Shade (Beautiful Immortals #6)
Genre: Paranormal fantasy
Date released: June 14th, 2015
Released by: Ravenwoodgreys
Blurb: From Tim O’Rourke #1 bestselling author of ‘The Kiera Hudson Series’ comes ‘Werewolves of Shade’ a werewolf romance with a twist.
When the entire population of Shade go missing, investigative reporter Mila Watson knows this could be the big break she has been waiting for. Setting off into the mountains to the village of Shade, Mila soon learns that the village isn’t as deserted as she first believed it to be and that creatures lurk in the shades…
‘Werewolves of Shade’ (Part Six)
Note: This ends in a cliff-hanger. Part Seven will be published within the next few weeks.
Picking up from where we left off in Werewolves of Shade (part 5), Mila is faced with walking straight into vampires that are now in Shade. With Calix, Rush, Rea and Trent by her side, Mila has to pluck up the courage and move swiftly in fighting off the vampires if she is to live and help protect her new friends. This is all quite a shock to Mila who was told that a witch had ended the war between the werewolves and vampires. Now, it appears that not everything was quite what she thought.
There is also a slight niggle in Mila’s thoughts that she may not be being loyal to the right people. After managing to shoot at a vampire she begins to question who she should be helping. But Calix, Rush, Rea and Trent have never done anything to make her feel that she shouldn’t help them. After all, they gave her somewhere to live, a job and helped in protecting her and defending herself. Maybe staying in Maze would have been the safest option, but she was so desperate to find out what had happened to her parents, and was happy to prove her independence and being able to think for herself by going to Shade.
In the heat of the action, shouts and gunfire, Mila is taken by a vampire and tied to a wooden, pole where she believes she will be burned alive. After banging her head, she drifts in and out of consciousness, and therefore, initially, not fully alert to the danger that she is in. The reader really feels fearful for Mila as a way out doesn’t seem possible.
“Was I now going to be ripped to shreds…? Would Calix and the others later find me dead – with my throat torn out and drained of all my blood?”
During her time tied up, we have a flashback of when Mila was back in Maze, when her uncle used to be away from home for a few days, and she would spend time as a young teenager with her boyfriend, Flint. These moments highlight the relationship she had with both Flint and her uncle, and how life has changed for her recently. She knows for sure that although she cared for Flint, he is not the one she is in love with. And, regarding her uncle, she cannot be certain why he didn’t tell the truth about the Beautiful Immortals. Did he know himself? Surely he must?
The writing is absolutely flawless as the reader is gripped with every moment that passes. The action, adventure, mystery and some brutal moments make it a very striking read that you will not forget in a hurry. But, as well as that, the reader also experiences every emotion there is when reading any O’Rourke story. The thrills and fear kick in, not to mention the rage that overcomes Mila during the gunfight at the beginning. There is also a comment from Calix that made me laugh that I’ll leave you to find!
This final instalment of the Beautiful Immortals series 1 holds many revelations as a great deal comes to light. Some I was half expecting but then others were a complete surprise, with a fantastic twist at the end. It is a brilliant end to the series as Tim O’Rourke loves to gobsmack his readers and leave them waiting for more…
A copy of Werewolves of Shade (Part 6) (Beautiful Immortals series 1) was provided by the author in return for an honest and fair review.
It is now available at Amazon UK and Amazon US.
Links to my reviews of previous instalments :-
Posted in Fantasy, Mystery, Paranormal, Review, REVIEWS (ALL) - Reverse Chronological Order, Werewolf theme
Tagged Beautiful Immortals Part 6, paranormal fantasy, review, short story, short story series, Tim O'Rourke, vampires, werewolves, Werewolves of Shade (Part 6)
As we begin this fourth instalment of the short story, paranormal fantasy series, Werewolves of Shade, we notice early on that the terror is turned up a few notches, sending fear to an incredible level. There is certainly more mystery to come, but with this added level of horror you’ll certainly be wanting to lock your doors and hide down under those covers as much as possible…
Release date: April 4th, 2015
‘Werewolves of Shade’ (Part Four)
Note: This ends in a cliff-hanger. Part five will be published within the next few weeks.
This is another winner for me, and yet more proof that Tim O’Rourke‘s writing is better than ever. To be able to pack a short story with so much emotion, mystery and horror, as well as to keep the reader informed of the plotline is amazing, and Werewolves of Shade has it all. In the latest instalment the horror is built up tremendously, the excitement is terrific, and the intensity is dark and profound.
One of the most surprising turn-ups is Clarabel, the twin sister of the recently deceased Annabel. Being the new teacher in the village, Mila is aware that Clarabel hasn’t attended school and she has never seen in her in the village before. After being given the reason that Clarabel has been absent due to illness, Mila’s suspicions still run high as it still doesn’t explain that there are ten seats in the class when surely there should be eleven?
Nobody had mentioned Clarabel before. Her intimate talk with Rush the previous evening doesn’t quite make sense now. He knew she was upset about Annabel’s death, they’d talked about it at length. Yet Clarabel was never mentioned! He’d also previously told her that the last school teacher had been some old woman, and yet now a younger Julia Miller has been mentioned. But why would Rush have lied to her?
Not only that but Mila is also left questioning her thoughts after a terrifying experience with the wolf who stands outside her cottage. She wakes the next morning unable to remember certain events, and so surely it must have been a dream? However, some evidence suggests that the ordeal was as real as it felt! Did she really see the wolf change shape? How did her nightie get torn to shreds? And, where did those scratches that make the full length of her back come from?
There are more twists to come as Mila tries to figure out if Rush has lied to her, and if so, why? Can she really trust gravedigger, Augustus Morten? And Calix – is he really as grotesque and annoying as he seems?
This whole instalment kept me gripped and on my toes, with some terrific scenes of horror, some scenes heightening in the heat level, and plenty of mystery as always with O’Rourke. That said, the biggest dread of all for Tim’s readers is the wait until the next instalment (due May 16th 2015)!
A copy of Werewolves of Shade (Beautiful Immortals #4) was provided by the author in return for a fair and honest review.
You can purchase Werewolves of Shade #4 at Amazon UK and Amazon US.
Posted in Fantasy, Mystery, Paranormal, Review, REVIEWS (ALL) - Reverse Chronological Order
Tagged fantasy, horror, mystery, paranormal, review, Tim O'Rourke, werewolves, Werewolves of Shade, Werewolves of Shade (Beautiful Immortals #4), Werewolves of Shade part 4
March 5, 2015 by Caroline Barker
Released on 1st March 2015 by Tim O’Rourke, #1 bestselling author of ‘The Kiera Hudson Series’, came ‘Werewolves of Shade’ (Part Three), a werewolf romance with a twist.
This short story series is getting darker! Despite there being so much adventure, there is always a great deal of mystery in Tim’s books, and part 3 of Werewolves of Shade is no exception! Thus far, Mila has left her uncle and best friend/boyfriend in the village of Maze, seeking her parents or what has become of them in the village of Shade. After hearing stories of the beautiful immortals, finding out about the war between the vamps and the wolves, and then hearing a possible myth that a witch ended it all, Mila has come to seek the truth. Believing Shade to be deserted she soon finds out otherwise and meets with Calix, Rea and Rush. This is a MUST-READ series for fans of paranormal, mystery, romance and even horror!
Assigned to replace the former village teacher, Mila has to meet the village children at the school. But she first needs to tackle the dark, mysterious alley where we left her at the end of Werewolves of Shade (Part 2). Not only does it feel claustrophobic and menacing, it seems to almost move and reach out to her – it actually put me in the mind-set of the never-ending alleyway in the film, The Labyrinth, albeit more menacing and terrifying! And just who is it who keeps calling her name? Surely it can’t be all in her head?!
Before she realises it, and not being able to explain how, she ends up on the other side where she meets with a most mysterious man in Augustus Morten. Although appearing to be friendly and kind towards Mila, the reader can’t help but be suspicious of him. As he walks Mila to the school it becomes apparent that he has spoken with Rea and knows a little about Mila. Is he talking to Mila to discover any holes in her story, or is he merely trying to be a friend? Finding out Augustus had been assigned as the village gravedigger made his character to be even more eerie.
The children of Shade seem fairly quiet as Mila begins to learn their names. Although speaking English she is surprised to realise their exercise books are all written in another language she has never seen before. And after, asking some questions, she realises that the children are not as open as she hoped. The story takes a turn when one child tries to answer Mila and is quietened by another. This begins to raise even more suspicion of the people of Shade with both Mila and the reader.
There is certainly more horror and gore in this instalment, following an unfortunate twist of events. But what will Mila make of it all? Is she partly to blame, and even if not, being the new stranger to the village raises suspicion and doubt of her. She is certainly going to have to gain the trust of people there.
Whilst Calix is still quite mean and sharp towards Mila, she can stand up to him. He gets under her skin and irritates her so much. Not forgetting the times when he seems a little full on and gets carried away with Mila, making for some very creepy and cringe-worthy moments! However, I can’t say that I completely dislike him, although a part of me tells me I should. There are times when I feel that his character may open up more and you could change your mind about him.
The one comfort in Shade that Mila has is Rush. He manages to subdue Calix a little and calm the situation, and make sure Mila is alright. They become increasingly close and open up to each other more. There are clearly feelings towards each other, but what of Flint, Mila’s boyfriend and best friend in Maze? Does she really love Flint or are they just friends? Is there really anything happening between Mila and Rush?
Part 3 is another fast-paced adventure with Mila getting deeper and deeper into her life in Shade. With a house, a job and a closeness to Rush, I do ask myself ‘will she ever be able to leave’? If so, how? And what will be her reason for leaving? But before we reach these answers, the biggest questions of all is ‘will she seek what she came to find?’ and ‘will she survive?’
The final twist and cliff hanger in this third instalment of Werewolves of Shade will leave you needing a change of underwear! It is petrifyingly brilliant, psychologically disturbing, just sheer horror that will leave you chilled to the bone!! And to extend the torture, we’ll have to wait until April 4th, 2015 for the next instalment!!!
A copy of Werewolves of Shade #3 was provided by the author in return for an honest and fair review.
Werewolves of Shade (Beautiful Immortals #3) by Tim O’Rourke is available at Amazon US and Amazon UK.
Posted in Horror, Mystery, New Adult, Paranormal, Review, REVIEWS (ALL) - Reverse Chronological Order, Romance
Tagged horror, mystery, paranormal, paranormal-romance, review, romance, short story, Tim O'Rourke, werewolves, Werewolves of Shade, Werewolves of Shade (Part 3)
February 5, 2015 by Caroline Barker
**REVIEW** Werewolves of Shade (Beautiful Immortals, Part 1) by Tim O’Rourke
From Tim O’Rourke #1 bestselling author of ‘The Kiera Hudson Series’ comes ‘Werewolves of Shade’ a werewolf romance with a twist.
Note: This ends in a cliff-hanger. Part Two will be released 13th February 2015 and is now available for pre-order.
Another brilliant read from Tim O’Rourke! I love how he packs so much into this short, 72 page paranormal romance. Werewolves of Shade, part one of the Beautiful Immortals series is also a mystery with a hint of horror that is fast paced and will keep you on your toes. Every time I pick up an O’Rourke book I feel a sense of excitement as they never fail to impress and intrigue, with fantasy running through every single read!
In Werewolves of Shade the reader cannot help but sympathise with Mila Watson. After being brought up through her teenage years by her uncle after the disappearance of her parents, she has never let go of her curiosity and need to find out exactly what happened to them as they had left to investigate the village of Shade and never returned.
The war between vampires and werewolves was long over, but left the towns and villages in ruins. It was only a myth that a witch had had a part to play in the ending of the war. But was she real, or was it purely a myth? As Mila has grown into a fine young woman and discovered the truth of her missing parents she needs to find out exactly what became of them and to investigate the myths surrounding the vamps, wolves and possible witch!
But will she really find it so easy to leave her uncle behind? After all, he has brought her up, cared for her, taught her to be the person she is. And then there is Flint. Her best friend, her lover, and the one person she has been able to grow up with, confide in and share her time with. Are they together because they are close friends and need to feed their desires, or is it really love?
As well as being a beautiful love story and paranormal mystery there are scenes of action and a little violence. I LOVE how short and snappy Tim writes, straight to the point, the heart of the scene. This allows the reader to imagine every second as you get pulled in and feel the fear, panic and intensity. The characters are so easy to like and understand, and the mystery keeps you guessing.
The cliffhanger is brilliant and I can’t wait to read part 2 of the Beautiful Immortals. Whether you’re an O’Rourke fan already, or simply looking for a new paranormal romance with mystery you’ll love Werewolves of Shade!!
A copy of Werewolves of Shade was provided by the author for the purpose of an honest and fair review.
Werewolves of Shade (Beautiful Immortals, Part 1) by Tim O’Rourke is available at Amazon US and Amazon UK.
Posted in Mystery, Paranormal, REVIEWS (ALL) - Reverse Chronological Order
Tagged Beautiful Immortals Part 1, paranormal, review, Tim O'Rourke, vampires, werewolves, Werewolves of Shade
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What's your favorit...
What's your favorite Tesla Model?
atlemacks
(@atlemacks)
General Admin
Personally, I have always really liked the old Roadster. When it was launched into space on the Falcon 9 Heavy, it inspired me to start saving for my elaborate funeral in ~60 years. I want to be launched into space on a SpaceX rocket and just ejected into space when I die. With the Metallica song "Now That We're Dead" playing on the livestream.
Anyways, my favorite current production model has to be the Model S. Even though it's barely been refreshed in minor ways, I still think it has a great look! I have been pricing solar for my home, and while Tesla doesn't offer their systems here, I can get a powerwall from them. The broadest part of my roof faces SE, and with 16 panels with the highest efficiency, I would produce a theoretical 117% of my usage needs. That 17% should be more than enough to charge the car without drawing from the grid. Baby steps, I don't have the money for the projects yet, but it's very promising the direction solar power and electric cars are moving.
CEO & Owner of Lemacks Media. Founder of Armed Forces Car Club.
Topic Tags: Model S (1),
Personally, I have always really liked the old Roadster...
Copyright © 2020 Armed Forces Car Club. All Rights Reserved. Google G Suite Services by Lemacks Media
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Organizations, Groups, Time Masters,
For the organization's successor, see Time Bureau.
Protecting the timeline from time pirates and time criminals (façade)
Manipulating the timeline for Vandal Savage (true goal)
"As a Time Master of long standing, you seem to forget our responsibility is to protect the timeline, not humanity."
—Time Master councilor to Rip Hunter[src]
The Time Masters was an organization (apparently) tasked with protecting the timeline, the Time Masters were also associates of Vandal Savage. Although the organization states that it's goal to keep the timeline, it was ultimately nothing more than a façade, as they used a device called the Oculus that would give them a vision of the "true timeline", but the senior members used it to manipulate the timeline, something that most members of the organization are not aware of.
Following the destruction of the Oculus, the Time Masters' ability to analyze and manipulate the timeline has been crippled, the Time Masters became inactive, they no longer were a force to protect the timeline, which prompted the Legends to take their place; until Rip Hunter founded an organization known as the Time Bureau.
The HQ of Time Masters in the Vanishing Point.
Rip Hunter stood before the council, requesting a team to take on Vandal Savage and prevent him from massacring any more people. However, the council turned a blind eye, standing by their decision. Instead, Rip took his timeship, the Waverider, and took on the mission anyway, in doing so relinquishing his position as a Time Master. They subsequently sent Chronos after him, to bring him in.[1]
Chronos followed the team, but failed again, and so Time Master Zaman Druce was sent to try and bring in Rip and his entire team. Druce pretended to offer Rip and his team amnesty, but when Rip seemingly conceded, Chronos turned up to execute him. However, Mick Rory forewarned Rip of the betrayal and, assisted by Firestorm, thwarted Druce and Chronos, forcing them to flee.[2]
Ultimately, Rip's team was able to capture Savage in 2166, along with evidence that he was tampering with time to acquiring futuristic technology for his conquest of Earth. Despite this justifying Rip's mission to stop Savage, it was revealed that the Time Masters have sided with Savage, believing him to be crucial to the balance of the timeline, opting to return him to 2166 and imprison Rip and his team.[3]
The Time Masters then captured every member of the team except Leonard Snart, Sara Lance, and Jefferson Jackson. They released Kendra Saunders and Scythian Torvil into Savage's "care". They also planned to brainwash Rory into becoming Chronos. Druce, in order to get Hunter to abandon his obsession, showed him the Time Masters' ace in the hole, the Oculus, a device that could be used to influence decisions. He explains not only has he been controlling the teams' actions for months but also that he was the mastermind behind Savage's rise to power, wanting Savage to take over the world in order to prepare the Earth's armies for an alien invasion in 2175.
Subsequently, Sara and Snart sabotage the Time Masters' time fleet before freeing their teammates; Rory revealed himself to have resisted being brainwashed before killing Time Master Declan. Druce anticipated that Rip would try to target the Oculus Wellspring to free his team from his manipulations and thus set an ambush, claiming it to be destiny. However, Jax appeared unexpectedly, having returned from early 2016, enabling the team to get to the wellspring. Though the Oculus had predicted that Ray Palmer would sacrifice himself to destroy it, Rory took his place, then Snart. Druce was helpless as Snart defiantly destroyed the Oculus, killing Druce and crippling the Time Masters' ability to analyze and manipulate the timeline.[4]
The Time Masters became inactive, and some of them were dead. They no longer became a force to protect the Timeline, which prompted the Legends to take their place.
Rip Hunter went on to create the Time Bureau to replace the Time Masters and ensure that they are void of the corruption of his former masters.
Sometime after the destruction and disbandment of the Time Masters, Rip Hunter, a former member of the organization, founded an organization known as the Time Bureau, whose goal is to truly protect the timeline. Unlike the corrupt Time Masters; the Time Bureau is based on morals, honor and principles.
Known members
Eve Baxter (inactive)
Miranda Coburn (resigned; deceased)
Zaman Druce (deceased)
Declan (deceased)
Rip Hunter (turned enemy; deceased)
Known allies
Former allies
The Hunters (bounty hunters; deceased)
The Pilgrim (assassin; deceased)
Mick Rory/Chronos (bounty hunter; resigned)
Vandal Savage (deceased)
Known enemies
Jefferson Jackson/Firestorm
Martin Stein/Firestorm (deceased)
Rip Hunter (former member; deceased)
Sara Lance/White Canary
Ray Palmer/The Atom
Mick Rory/Heat Wave (former ally)
Kendra Saunders/Hawkgirl
Scythian Torvil/Hawkman
Kaylex Druzan (deceased)
Carter Hall/Hawkman (member of the Legends; deceased)
Leonard Snart/Captain Cold (member of the Legends; deceased)
"Pilot, Part 1"
"White Knights" (Zaman Druce)
"Marooned"
"Left Behind" (mentioned)
"Progeny" (mentioned)
"The Magnificent Eight" (mentioned)
"Last Refuge"
"River of Time"
"Destiny"
"Legendary" (mentioned)
"Out of Time" (mentioned)
"Abominations" (mentioned)
"Raiders of the Lost Art" (memory)
"The Legion of Doom" (mentioned)
"Turncoat" (mentioned)
"Camelot/3000" (mentioned)
"Land of the Lost" (flashback)
"Aruba-Con" (mentioned)
"Return of the Mack" (mentioned)
"Crisis on Infinite Earths: Part Four" (mentioned)
Time Masters use aliases to prevent their ancestors, descendants, and loved ones from becoming targeted by their enemies.
The Time Masters were nicknamed "Time Bastards" by Leonard Snart, and called "Time Pigs" by Mick Rory.
Rip Hunter claims that the Time Masters were aware of Mallus, that he was an evil, ancient and powerful, meaning at some point they encountered him when time was broken. However, he also says that the Time Masters "dared not speak his name", and considering that would mean they never said his name and that the organization is inactive, he may have just added them in to lend credibility to his statement.
What happened to the surviving Time Masters is open to debate.
They could be funding time pirates for self-gain
Or they could have been killed for their time travel technology.
Have retired to secluded places in time to avoid the Legends
In DC comics, Time Masters are a heroic team led by Rip Hunter, rather than a villainous one hunting him as a rogue member.
Unidentified Time Masters are portrayed in "Pilot, Part 1"" by Mackenzie Gray, Simone Bailly and Christopher Logan.
↑ "Pilot, Part 1"
↑ "White Knights"
↑ "River of Time"
↑ "Destiny"
Retrieved from "https://arrow.fandom.com/wiki/Time_Masters?oldid=607573"
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Objects, Drugs, Allusions to the comics
Velocity serums
Hunter Zolomon (Velocity 6)
Harrison "Harry" Wells (Velocity 1-6)
Caitlin Snow (Velocity 6-9)
Eliza Harmon (Velocity 9)
Cisco Ramon (Velocity X)
Hunter Zolomon (formerly; deceased)
Eliza Harmon (deceased)
Jesse Wells (unwillingly; formerly)
August Heart
Barry Allen (unwillingly; formerly)
Increase a user's speed
"Zoom never stole your speed. This is what's making you sick. Velocity-6 is killing you."
—Dr. Caitlin Snow realizing the cause of "Jay Garrick's" disease[src]
Velocity is a series of drugs that allows temporary access to the Speed Force. Initially developed by Hunter Zolomon and then by Dr. Harry Wells as Velocity 6, the current version of the drug (Velocity 9) was created by Dr. Caitlin Snow. Despite its benefits, this drug is also very dangerous, as it causes cellular degeneration and eventually death. In addition, subjects of the serum have demonstrated mental instability or disorder, such as the split personality Eliza Harmon developed.
Wells first started to develop a speed-enhancing drug after Zoom appeared on his Earth, and it was meant to aid "Jay Garrick" in his struggles against the super-villain Zoom. However, the first five attempts (Velocity 1 to 5) were failures. A version of the drug, created by "Jay", seemingly caused the loss of his powers, as well as his cellular degenerative disease. In reality, "Jay" had in fact increased his speed, but at the cost of cell degeneration, forcing him to seek new, untainted sources of the Speed Force.
The drug was first mentioned by Harrison "Harry" Wells after he had traveled to Earth-1 and joined Team Flash. He explained its history to Caitlin Snow. She helped him create a successful version of the drug with her expertise in biochemistry. They produced the sixth version of the drug by adding sodium chlorate, as the drug needed an extra release of oxygen to function.
Though initially appearing reluctant to use the Velocity 6, "Jay" took the drug in order to save Wells after he had been shot by Patty Spivot. When Wells later thanked "Jay" for saving his life, the speedster however told him to keep the drug away from Barry.[1]
When Barry had traveled to Earth-Two, Central City was attacked by Geomancer, and "Jay Garrick" had to take Velocity 7 to stop him. Due to the new serum's short-lived effects, Caitlin made Velocity 8, but was forced to update the formula due to the problems with Velocity 8. Velocity 9 was the first version of the compound to seemingly cause no side-effects, and it also triggered "Jay"'s latent regenerative abilities, temporarily stopping his cellular degeneration. Velocity 9 lasted long enough for "Jay" to save the day in Barry's absence.[2]
During Velocity 9's development, Caitlin had asked Eliza Harmon for help, as she was having trouble with the synthesis. She sent information on 3 of the 8 components to Eliza. Eliza reverse engineered the drug, and used it to gain super-speed. The drug caused Eliza to develop an immoral split personality which became Trajectory, as well as an addiction to the drug which manifested as the voice of Trajectory in Eliza's head. At Star Labs, Trajectory held Caitlin, Cisco, Harrison and Jesse hostage in order to obtain more Velocity 9. She injected Jesse Wells with Velocity 9. This was to ensure the drug worked and wasn't a trick but, Jesse was injected with too much and began to experience an overdose. Jesse's father, Harry, saved her life by undergoing a blood transfusion to flush the drug from her system.
As Trajectory's body disintegrated, due to accelerated cellular degeneration as a result of not having a natural connection to the Speed Force, her lightning turned blue. This, coupled with knowledge about "Jay's" illness, led the team to deduce that Zoom had taken the Velocity drug and was dying, leading to the discovery of Zoom's secret identity as Hunter Zolomon, who masqueraded as both Zoom and "Jay Garrick" all along to increase and then steal Barry Allen's speed, curing himself from cell degeneration.[3]
At some point, Cisco created Velocity X and hid vials of it inside of the pinball machine. When Barry's speed healing was disabled after being infected by Ramsey Rosso, Cisco ran off to get a vial of Velocity X and injected Barry with it to bolster the Speed Force within him in an attempt to help the Speed Force fight for control of Barry against Russo's infection. This version of the drug has shown no side effects in Barry but was presumably kept secret from him due to it being untested and therefore still dangerous to use until it became Team Flash's only option to save him from Ramsey.
In 2049, August Heart presumably recreates the Velocity 9 serum and uses it to steal chemicals while known as Godspeed, artificially becoming a speedster. He wanted to create a Velocity serum that can last forever so he also wanted a stabilizing agent however, he was stopped by Nora West-Allen with help from Eobard Thawne. August used tachyons with the Velocity 9 which made his lightning white, and was one ingredient short, a binding agent, of creating a permanent Velocity serum that would last forever and not wear off.
The drug temporarily increases the user's speed beyond normal limits and this speed far exceeds the speed of the Flash at Mach 2.2. The drug has several side-effects, a highly addictive drug, it causes rapid cellular degeneration, in one case, the user developed a psychotic second personality that caused her to commit criminal acts. At some point, the drug causes the lightning generated by a speedster to turn from the usual yellow into blue,
Zoom emitting blue lightning, a side-effect of using the Velocity drug.
also, as seen with Hunter, users of this drug can make their voice sound monstrous and can turn their eyes black.
Certain versions of the drug had more problems, "Jay Garrick's" version of Velocity 6 caused him to lose his connection to the Speed Force and the cellular degeneration he had suffered was slowly killing him, Velocity 7 granted super-speed for too short a time, Velocity 8 had numerous kinks, which led to the immediate development of Velocity 9. While Velocity 9 initially seemed to cure the damage caused by the previous versions by also amplifying one's healing powers, it only delayed the symptoms caused by Velocity 6 (though apparently do not have any degenerative side effects of it's own).
Because Zoom lived a long time with blue lighting, but Eliza lived for only a few seconds with blue lighting, it's implied that a natural connection to the Speed Force is able to slow down the cellular deterioration caused by the serum.
Possible future
In 2049, August Heart was stealing chemicals as Godspeed in order to make his own Velocity 9, the chemicals he stole include benzene methanol, carbon disulfide and dioxygen difluoride which create the base for the speed drug, a stabilizing agent was all that he needed to make the drug's effects last forever, it is presumed that he also stole sodium chlorate, the most important component of Velocity 9 due to the large quantity of oxygen it releases, August's version of the drug coupled with tachyons made the blue lighting generated from the serum turn white.[4] Whether he found a way to stop the cellular degeneration that the drug causes is unknown.
Users of the drug are vulnerable to radio waves. In 2049, when Godspeed fought Nora West-Allen, she used this fact to stop the villainous speedster. Radio waves disrupt the bonds that hold the V-9 together, causing it to break down very quickly and strip the user of their powers instantly.
Barry Allen/The Flash/Dark Flash
Eliza Harmon/Trajectory (deceased)
August Heart/Godspeed
Hunter Zolomon/The Flash/Zoom (formerly; deceased)
"Legends of Today"
"Welcome to Earth-2"
"Escape from Earth-2"
"Trajectory"
"The Race of His Life" (flashback)
"Godspeed" (flashforward)
"The Last Temptation of Barry Allen, Pt. 1"
In the DC comics, Velocity 9 was a drug created by Vandal Savage that granted a temporary speed enhancement. It was sold in the illegal drug trade. It too had severe side-effects.
Another variation called Speed Juice exists in the comics as well. This variation is the power source of the pre-Flashpoint Johnny Quick, the Flash's counterpart from the Antimatter Universe and a member of the Crime Syndicate (not to be confused with the Golden Age speedster of the same alias).
↑ "Legends of Today"
↑ "Escape from Earth-2"
↑ "Trajectory"
↑ "Godspeed"
Retrieved from "https://arrow.fandom.com/wiki/Velocity_serums?oldid=580659"
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Morning Spark
Daily Impact
FOLLOW A PLUS
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You’ll Never Work In This Town Again…
"If this is happening to me, it is happening more aggressively to women everywhere."
"You'll never work in this town again."
A cliché to be sure, but also what a producer threatened when I refused to pose semi-naked on the cover of a men's magazine to promote our film. I was no longer willing to subject myself to a naïve compromise that I had previously been willing to. "I will never work in this town again?" I was livid, I felt objectified, and for the first time in my career I said "no." And guess what? The world didn't end. The film made a lot of money and I did work in this town again, and again, and again. What this producer may never realize is that he spoke aloud the exact fear every woman feels when confronted with gender bias in the workplace.
It's what we are conditioned to believe — that if we speak up, our livelihoods will be threatened; that standing our ground will lead to our demise. We don't want to be kicked out of the sandbox for being a "bitch." So we compromise our integrity for the sake of maintaining the status quo and hope that change is coming.
But change is not coming fast enough to help my friends, my peers, or even our children. In fact, a recent study by the American Association of University Women shows that the pay gap is closing at such a slow rate that it will be 136 years before women are paid equally to men. 136 years. And the pay gap is but one clear quantification of the acute undervaluing of the contributions of women in the workplace.
Throughout my career, there have been moments when I have been insulted, sidelined, paid less, creatively ignored, and otherwise diminished based on my gender. And always, I tried to give people the benefit of the doubt; maybe they knew more, maybe they had more experience, maybe there was something I was missing. I taught myself that to succeed as a woman in this industry I had to play by the rules of the boy's club. But the older I got and the longer I worked in this industry, the more I realized that it's bullshit! And, worse, that I was complicit in allowing it to happen.
So, I started my own club. I formed a production company with three amazing women. We have been hustling to develop quality television shows with unique voices and perspectives. Since our inception, we have been lucky enough to partner with incredible producers, male and female, who have treated us as true equals and partners. Recently, we signed on to partner with an influential male producer on a project that would shine a light on an important social issue — ironically — inclusivity and our shared human experience.
In the process of pitching this show to a major network, the typical follow-up emails were sent to executives at this network. In this email chain, this producer chose to email the following:
"And Mila is a mega star. One of biggest actors in Hollywood and soon to be Ashton's wife and baby momma!!!"
This is the entirety of his email. Factual inaccuracies aside, he reduced my value to nothing more than my relationship to a successful man and my ability to bear children. It ignored my (and my team's) significant creative and logistical contributions.
We withdrew our involvement in the project.
Yes, it is only one small comment. But it's these very comments that women deal with day in and day out in offices, on calls, and in emails — microaggressions that devalue the contributions and worth of hard-working women.
Subtle gender bias is oftentimes nearly imperceptible, and even wholly undetectable to those who share the bias. It became clear in later emails from this producer that he was totally unaware of why his words were so appalling. What he characterized as a "lighthearted" comment was actually deeply undermining to my contributions and ability to be taken seriously as a creative partner.
I have no interest in vilifying this man. Blind gender biases are embedded in every facet of our life. They are reinforced by our educational institutions: men dominate the figures we study in history, the luminaries of math and science and technology about whom we learn, and the authors of political discourse we are taught to revere. We are inundated with tales of male superiority that blind us to the architecture of our own relationships. The very word "blind" informs us of everything. No one gets upset when a blind person bumps into a wall, but the wall does not cease to yield force.
I'm done compromising; even more so, I'm done with being compromised. So from this point forward, when I am confronted with one of these comments, subtle or overt, I will address them head on; I will stop in the moment and do my best to educate. I cannot guarantee that my objections will be taken to heart, but at least now I am part of creating an environment where there is the opportunity for growth. And if my comments fall on deaf ears, I will choose to walk away.
If this is happening to me, it is happening more aggressively to women everywhere. I am fortunate that I have reached a place that I can stop compromising and stand my ground, without fearing how I will put food on my table. I am also fortunate that I have the platform to talk about this experience in the hope of bringing one more voice to the conversation so that women in the workplace feel a little less alone and more able to push back for themselves.
I will work in this town again, but I will not work with you.
Cover image via Featureflash Photo Agency / Shutterstock.com. This story originally appeared on Medium.
Tags: sexism, ashton kutcher, mila kunis, women in the workplace, gender bias
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Atrium Health Foundation Receives $2 Million Gift for Sanger Heart & Vascular Institute
01.07.2020 Atrium Health News | Sanger Heart & Vascular Institute
CHARLOTTE, N.C., December 18, 2019– Atrium Health Foundation has received a $2 million gift from the California-based William, Jeff, and Jennifer Gross Family Foundation to help Atrium Health’s Sanger Heart & Vascular Institute initiate change and fundamentally transform cardiovascular care in the region.
The gift from the William, Jeff, and Jennifer Gross Family Foundation – the charity founded by retired asset manager Bill Gross (pictured top right) and his son and daughter – will launch the Center for Cardiovascular Care Transformation at Sanger. The Center will be the driving force for innovation in education, research, and clinical care pathways necessary to support foundational change in the delivery of cardiovascular care in the greater Charlotte region. It will be housed in the new Sanger Heart & Vascular Institute – Kenilworth location, currently under construction adjacent to Atrium Health’s Carolinas Medical Center Campus.
For the Gross family, the gift is personal. “Thanks to Sanger and Bill Downey, MD (Vice Chair of Quality and Care Transformation, pictured middle right), my mother-in-law received lifesaving care after suffering a heart attack,” said Jeff Gross. “We are forever grateful for Dr. Downey’s expertise and are thrilled to make this donation to benefit others who are in need of the best heart care."
To keep pace with the continuous change in cardiovascular medicine, the elements that define care evolve rapidly, often resulting in variation in the quality of care delivered. Adding to this challenge is next decade’s projected growth of over 20 million Medicare patients—many of whom will have cardiovascular care needs. The new Sanger Center for Cardiovascular Care Transformation will address this by advancing the implementation of best practices into everyday clinical care, integrating virtual access and remote patient monitoring capabilities, and closing gaps in care within underserved communities.
“Currently there are few models of cardiovascular care delivery in the US that reliably provide ‘best’ care to all patients,” said Geoffrey Rose MD, Sanger President (pictured bottom right).
“Thanks to the generosity of the William, Jeff, and Jennifer Gross Family Foundation, we will be able to develop and implement novel approaches that will not only benefit patients here in our region but also those in other health systems across the country.”
About Sanger Heart & Vascular Institute
Sanger Heart & Vascular Institute has been committed to delivering world-class cardiovascular care for more than 50 years. Founded by Francis Robicsek, MD, a pioneer in cardiac surgery, Sanger’s history is one of innovation. Sanger physicians continue that legacy today through early adoption of the most advanced technology available in the world and the advancement of new treatments. Sanger’s nationally and internationally recognized experts provide patients access to the most comprehensive care, ranging from general cardiology to the highest surgical complexity, including adult and pediatric heart transplant programs.
About Atrium Health
Atrium Health, previously Carolinas HealthCare System, one of the nation’s leading and most innovative healthcare organizations, provides a full spectrum of healthcare and wellness programs throughout North and South Carolina. Its diverse network of care locations includes academic medical centers, hospitals, freestanding emergency departments, physician practices, surgical and rehabilitation centers, home health agencies, nursing homes and behavioral health centers, as well as hospice and palliative care services. Atrium Health works to enhance the overall health and wellbeing of its communities through high quality patient care, education and research programs, and numerous collaborative partnerships and initiatives
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Vote No to Scottish independence!
Submitted by AWL on 3 September, 2014 - 1:48 Author: Editorial
On 18 September the people of Scotland will decide whether or not to become an independent state.
Latest polls show 47.6% against Scottish independence with 41.6% in favour, and 10.8% undecided. Opinion against independence has dropped, numbers undecided have dropped, and support for independence has risen. Discounting the undecided, 53% are against and 47% are for independence.
Much of the British left is disoriented on the issue, making their political compass crass anti-Toryism rather than a reasoned assessment of the issue. Many claim that an independent Scotland would be more left wing, would not pass on Westminster cuts, and would be more responsive to class struggle in Scotland. We should have no illusions that the Scottish bourgeoisie will be kinder to the working class!
This kind of anti-Toryism looks for short-cuts and wants to believe there are ways to circumvent building united class struggle across the border as the way to beat back the attacks we all face.
We favour of the right to self determination of national groups. And if the Scottish people were to vote for independence we would defend that right against “unionist” opposition.
However, generally we are in favour of taking down borders between people, not erecting them. We make the interests of the working class our priority, and a larger political unit of England, Scotland and Wales makes uniting the working class easier. This is the basis for a stronger labour movement and a stronger fight against the bourgeois state. This is the longer route, and in reality the only route to beating the Tories and the system they represent.
Scotland is not an oppressed nation. Independence for Scotland would remove no real oppression. The “rule of Westminster” that many in the Yes campaign (even socialists) claim oppresses Scotland is in reality the oppression of the working class throughout all of England, Scotland and Wales.
We are for a vote against independence. For a united Scottish and English working class to wage class war against their joint oppressor. For a federal republic in Britain and strong local autonomy for the Scottish people and others.
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The only referendum which should be decisive in Scotland in this election is a “referendum...
Solidarity 334, 3 September 2014Scotland
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You are here: Home › DiBella Leading New Montgomery Biscuits Ownership Group
DiBella Leading New Montgomery Biscuits Ownership Group
Richmond Flying Squirrels (Class AA; Eastern League) owner Lou DiBella is leading a group buying the Montgomery Biscuits (Class AA; Southern League) from Sherrie Myers and Tom Dickson.
The sale announcement comes with the usual list of conditions: it must be approved by the Southern League, Minor League Baseball and Major League Baseball. DiBella and Myers are optimistic the approval process could be completed before the beginning of the regular season in April — a process that certainly will be sped along because DiBella and other investors, which include Todd “Parney” Parenell, are known quantities as Flying Squirrels owners.
It doesn’t sound like much will change this season; it is a little late to do much anyway, and the Biscuits aren regarded as a well-run team. Myers and Dickson brought the team to Riverwalk Stadium in 2004 after spending several years in Orlando, and the franchise was a success from the beginning. From the Montgomery Advertiser:
DiBella declined to get into specific plans he has for Montgomery, but said he is an idea guy who will look to make his mark on the team and bring people to the stadium who had never been before.
“Minor league baseball is about fun, and it’s about relationships,” DiBella said. “Our goal is to get everybody working with us and for us to have fun, and we want that to trickle down to everybody who walks into the ballpark, and we want to be an impactful, important part of the community.”
About Kevin Reichard
Kevin Reichard is founder and publisher of Ballpark Digest.
View all posts by Kevin Reichard →
New Winston-Salem Dash Logo Unveiled
lou dibella, montgomery biscuits, richmond flying squirrels, southern league, todd “parney” parnell
First Look: Joker Marchant Stadium Renovations
BB&T Ballpark Could See More Development
Florida Fire Frogs to CoolToday Park for 2020 January 16, 2020
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Volume 18, 6 Issues, 2020
134th of 267 in
Current Vascular Pharmacology, Volume 4 - Number 4
Editorial [ The Metabolic Syndrome: Revisiting the Concept, the Diagnosis and the Treatment (Part-II) Guest Editors: John H. McNeill and Vijay Sharma ]
Permissions Order Reprints Order Eprints
The Etiology of Hypertension in the Metabolic Syndrome Part One: An Introduction to the History, the Concept and the Models
The Etiology of Hypertension in the Metabolic Syndrome Part Two: The Gene-Environment Interaction
The Etiology of Hypertension in the Metabolic Syndrome Part Three: The Regulation and Dysregulation of Blood Pressure
The Etiology of Hypertension in the Metabolic Syndrome Part Four: The Systemic Perspective – The Role of the Neuroendocrine and Immune Systems,and the Challenge of Integration
Leptin and Vascular Smooth Muscle
Recent Insights into the Role of Prostanoids in Atherosclerotic Vascular Disease
Lipid Modulation of Intravascular and Cellular Sodium Handling:Mechanistic Insights and Potential Clinical Implications
Dimitri P. Mikhailidis
(33295 citations)
Academic Head, Department of Clinical Biochemistry
Royal Free Hospital Campus
University College London Medical School
Pond Street
London, NW3 2QG
Biography of Dimitri P. Mikhailidis
Dimitri P. Mikhailidis graduated from the University of London (BSc, MSc, MB,BS and MD) and is Academic Head, Department of Clinical Biochemistry, Royal Free Hospital campus, University College London Medical School. He is also a Visiting Professor, University of Belgrade, Serbia and at two universities in Saudi Arabia. His research interests are dyslipidaemias and thrombosis. He is a Fellow of the Royal College of Pathologists (FRCPath), Royal College of Physicians (FRCP), Faculty of Pharmaceutical Medicine (FFPM) and American College of Clinical Pharmacology (FCP). He has 22,093 citations on the ISI index, Core Collection (H-factor 64).
⇨ Journal Home⇨ Editorial Policies⇨ Editorial Board⇨ Meet the Executive Guest Editor(s)⇨ Reviewer Board⇨ Board Recruitment Workflow⇨ Join Editorial Board⇨ Indexing Information⇨ Announcements⇨ Endorsements⇨ Authors' Comments
Current Vascular Pharmacology Journal was launched in 2003. Dr. Dimitri P. Mikhailidis serves as the Editor-in-Chief of the journal.
Scopus CiteScore Metrics: 1.73
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Time: 16:33 LT
Robinson R44 Raven
Owner/operator: Private
Registration: N616HS
C/n / msn: 10449
Location: James County, Williamsburg, VA - United States of America
Phase: Initial climb
Nature: Private
Departure airport: Williamsburg Jamestown (KJGG)
Destination airport: Stafford Regional Airport (RMN)
The aircraft impacted a residential building shortly after takeoff and a post-impact fire ensued in northwest Williamsburg, Virginia. The helicopter was destroyed and pilot plus one building occupant were fatally injured.
Several witnesses near the accident site described the helicopter as flying low, one estimated its height at about 100 feet above the ground, as it approached the two-story condominium complex. They described it as flying relatively straight and level or slightly descending, before suddenly pitching nose down and descending into the roof of the building. One witness described the helicopter as "rocking back and forth unsteadily" just before it pitched downward. Another witness located about 100 yards south of accident site recalled the engine making a "constant sound" as it flew over his head.
The helicopter impacted a two-story 10 unit condominium building located about 3 nautical miles north of JGG. The main wreckage came to rest inside the north end of the building, with some components including a section of the tail rotor drive shaft found along the 70-foot wreckage path extending from the building on a heading of about 20° magnetic.
https://wydaily.com/local-news/2018/07/08/aviation-crash-reported-in-williamsburg-neighborhood-firefighters-on-scene/
https://wtkr.com/2018/07/08/aviation-crash-reported-in-williamsburg-residential-area/
https://wtvr.com/2018/07/08/dillard-complex-williamirbug-helicopter-crash/
https://www.google.com/maps/place/1100+Settlement+Dr,+Williamsburg,+VA+23188/@37.2883027,-76.7297586,16z/data=!4m2!3m1!1s0x89b08961139c8fbf:0x5161a1cce4686f56?hl=en-us&gl=us
https://flightaware.com/live/flight/N616HS
https://wydaily.com/local-news/2018/07/24/preliminary-ntsb-report-reveals-new-details-about-deadly-williamsburg-helicopter-crash/
https://app.ntsb.gov/pdfgenerator/ReportGeneratorFile.ashx?EventID=20180708X12242&AKey=1&RType=HTML&IType=FA
http://registry.faa.gov/aircraftinquiry/NNum_Results.aspx?NNumbertxt=616HS
http://www.airport-data.com/aircraft/photo/000240488.html
Helicopter has crashed into a residential area in Williamsburg, Virginia causing a major fire. Fire department on scene. No info on casualties at this time.
🎥@scottgorslene pic.twitter.com/o0X0iNlTB8
— Tom Podolec (@TomPodolec) 8 juillet 2018
09-Jul-2018 04:05 Geno Added
09-Jul-2018 05:46 Iceman 29 Updated [Embed code]
09-Jul-2018 14:46 Captain Adam Updated [Total fatalities, Other fatalities, Embed code, Narrative]
09-Jul-2018 18:54 Captain Adam Updated [Registration, Cn, Operator, Total fatalities, Source, Narrative]
10-Jul-2018 01:02 Geno Updated [Phase, Departure airport, Source, Narrative]
10-Jul-2018 06:02 Aerossurance Updated [Time, Phase, Nature, Narrative]
25-Jul-2018 17:11 Aerossurance Updated [Time, Destination airport, Source, Narrative]
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Recorded coverage of the Culture, Media and Sport select committee hearing on press standards, from Tuesday 10 March. Westminster is currently in recess.
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About Blog Press Reports Tour Sign In
A Fresh Take on CRE
The Commercial Observer with CompStak Data: HookLogic Signs Sublease at 99 Hudson Street
Published on 29 October
to read ( words)
Media company signs new lease in TriBeCa!
HookLogic Signs Sublease at 99 Hudson Street
By Gus Delaporte 10/29 7:30am
Ecommerce media company HookLogic has signed a four-year, 11,721-square-foot sublease from BGB New York on the ninth floor at 99 Hudson Street, The Commercial Observer has learned.
The tenant will pay rent in the low-$50s per square foot, according to data from CompStak.
The rent HookLogic will pay is slightly higher than the BGB’s current rent for the space, which is in the high-$40s per square foot. The sublandlord, a biopharmaceutical marketing and advertising firm, signed a 10-year, 25,000-square-foot lease to relocate to 462 Broadway in Soho earlier this year.
HookLogic, which will relocate from 455 Broadway, closed last month on $14.3 million in Series B funding led by Intel Capital. In 2011, the company received $9.5 million in Series A funding from Bain Venture Capital.
With a focus on the retail, auto and travel sectors, HookLogic offers online advertising services to a variety of brands. In February, the company launched its Retail Search Exchange, a service that allows brands to bid for product ad inventory across multiple retail platforms. The company, which employs 95 people in its New York and Ann Arbor, Mich. offices, is also expanding its traditional service line into the consumer electronic, toy and home goods sectors.
With staff growth on the horizon—the company plans to hire between 15 and 25 employees on the technology and engineering teams in the coming months—HookLogic quickly realized its space in Soho could no longer accommodate the rapidly expanding company’s needs.
The tenant was represented by Sacha Zarba, Sam Spillane and Jeff Sharon of CBRE.
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HorseTourneys.com Blog
Use Site Credit
New User Offer – Play $75, Get $100
Howard Welsh Registers Friday and Sunday Triumphs; “Lex” Zepp Buys a Stairway to the BCBC (Weekend Recap October 18-20)
Posted on October 21, 2019 by ericwing
Howard Welsh isn’t averse to playing various NHC and BCBC qualifiers, but cash games are what he truly considers his sweet spot. And with results like he gets, who could blame him?
The New Jersey resident picked up a fast $4,876 in Friday’s 10-race $7,500 Guaranteed Pick & Pray. The tourney closed with a pot of $9,752, and Welsh made the game his own by recording four winners and two places. Chief among his triumphs was that of Minit Maus, who broke away from Courageous Cat long enough to score a victory in the 8th at Belmont that returned $57.00 to win and $17.80 to place.
Welsh didn’t have much luck on Saturday—but he did on Sunday.
Dennis Montoro ruled the roost in the day’s $10,000 Guaranteed cash game (final purse: $12,425) thanks to five firsts and four seconds, led by Better Charge It ($25.60, $9.00) in the 7th at Keeneland. With Sunday winnings of $6,212, Montoro shouldn’t need to charge things anytime soon. Welsh, meanwhile, had just a pair of wins and places, but one of those runners up was Cabertoss in the final tourney race, the 10th from Woodbine. Cabertoss paid $21.60 in the place slot and that got him up to second—good for a nice consolation prize of $2,485, that brought his weekend cash total up to $7,361.
Welsh is like the Chip Reese of handicapping contests. Reese was a famed cash-game specialist in the poker world.
You didn’t see Reese much in the televised tournaments. Single-table cash competitions were more his thing. Though he would occasionally dip his toe into other events—and so will Welsh.
Sunday’s $10,000 Guaranteed tourney and the same day’s Flo-Cal Faceoff qualifier were both live-format games, but Welsh played them like Pick & Prays, using the same picks in each. Here, Cabertoss’s strong showing got him all the way up to the top spot and rewarded him with a $1,500 Flo-Cal entry for next winter’s online event.
Howard Welsh
And, of course, the Flo-Cal Faceoff is a $100,000 Guaranteed all-cash tourney…so Welsh should feel right in his element there.
Getting back to Friday’s action, $75 NHC qualifiers have become a fixture at the end of the workweek. They tend to be popular with those who are double-qualified for the NHC because the entry fee is small, and fields are big—meaning that it’s fertile ground for NHC Tour points. That opportunity for Tour heavy heads, in turn, creates an opportunity for those still hunting for NHC spots.
The first- and third-place finishers in Friday’s $75 qualifier—Gregg Kingma and Jeff Bussan—already possessed two seats to the big bash at Bally’s next February, so that meant the NHC spots went to Thomas Blosser and Enrique Vazquez who checked in second and fourth, respectively. All four of the above counted 10th-race Keeneland victor Come on Venezuela ($14.80, $6.20) among their day’s successes.
It was a different, more lucrative Keeneland winner that was the common thread for the two winners in Friday’s Breeders’ Cup Betting Challenge Low Ratio qualifier at HorsePlayers.
Both Kevin Cox (3 wins, 1 place) and Anthony Kite (2 wins, 0 places) were flying high and ready for their close-ups after having Lightscameraaction ($41.60, $13.00) in the 8th at Keeneland. Neither player cashed anything in the last race, but they held on to earn the $10,000 entries.
There were two more Breeders’ Cup Betting Challenge qualifiers on Saturday at HorsePlayers—and let’s just say that to win them, you needed the luck of the Irish.
Thomas Murphy had four wins and a place to capture Saturday’s Super Low Ratio qualifier. I don’t believe that James Metzger (winner of the 2018 Woodbine Mile Horseplayers Tournament) is Irish, but what I meant in the last paragraph is that you needed to be Irish to finish first…not second. Anyway, Metzger is also headed to the BCBC thanks to three wins and two runners up.
There was also a “regular” BCBC qualifier on Saturday and, here, it was a different Murphy who dropkicked his opponents.
Just two weeks ago, the HorseTourneys world marveled at Justin Dew’s final score of $200.40 in the October 6 NHC Low Ratio qualifier. Murphy exceeded that sum with a gaudy total of $205.30, built on five wins and a place. Shamefully, Joseph missed out on the day’s highest-priced winner in the 10th at Keeneland. Nevertheless, we’ll offer up a look at his still-quite-spectacular scoresheet:
You’ll note that Tom Arndt was the token non-Irishman to also win a BCBC entry by finishing second to Murphy. You may have also noted that he used the four horse in each of the final ten races after picking “non-fours” in the first two.
We’re not sure if this was by design…or if Arndt entered the contest not realizing that it was a Pick & Pray and he only had time to handicap the first two. (Most of the weekend’s featured tourneys were, indeed, live-format games, but not this one.) In any event, we will point out that one of his “non-fours” was Mr. D’Angelo—the 17-1 winner of the 8th at Laurel.
There were plenty of longshots on Saturday (especially at Keeneland), so scores were similarly high in the three featured events at HorseTourneys. You basically needed to reach or come close to the $150.00 mark.
Michael Lynch Jr. came just 50 cents short of that total, though that was still sufficient to earn himself $8,387 in Saturday’s $17,500 Guaranteed tourney, which finished up with a purse of $18,638. Lynch had four winners, including the Keeneland bombs Tough Ima in race 8 ($38.40, $16.60) and Star of Kodiak in race 10 ($49.20, $15.60).
Exceeding the $150.00 plateau was Matthew Rentze.
Rentze put together six wins and a place to win the day’s NHC qualifier that was restricted to those without a seat. He capped things off by hitting…a capper…23-1 Star of Kodiak at Keeneland. Here’s how Rentze’s scorecard looked:
Timothy Jacobs, meanwhile, had just three winners on Saturday…
…but they were nice ones—going off at 17-1, 13-1 and 23-1—and that earned Jacobs the full-ride scholarship to the Horse Player World Series next March.
Sunday’s winning scores were all over the map. The day’s top performance was turned in by Ken “Special K” Kingsbury.
Kingsbury posted a Sunday-best $138.20 in winning the day’s regular NHC qualifier. He had five winners, including Latest Vision ($32.60, $15.60) in the 6th at Keeneland. He also had a pair of runners up including Magical Romance, who went off at a whopping 89-1 in the 10th at Belmont. Also picking up a Bally’s Berth was second-place finisher Blaise Guadagno who registered four cashes on top and one underneath.
On the other side of the spectrum, Jorge “Smooth” Cruz-Aedo needed just $59.20 to win our first qualifier to the December 7 Lone Star Park NHC qualifier.
It will be a “home game” on December 7 for Texas native Cruz-Aedo. He had just one first and two seconds…but one of those seconds was Magical Romance.
The other winning scores were somewhere in between those of Kingsbury and Cruz-Aedo. Evan Trommer needed six winners and a place to squeak out a $1.90 victory in Sunday’s NHC Low Ratio Pick & Pray.
Trommer’s biggest price was with Cooler Mike ($16.50, 6.40) in the Bunty Lawless Stakes at Woodbine. He was almost caught in the finale by Steve Simonovic when Lord Wimborne won the nightcap at Woodbine. But the win/place return of $7.20 and $4.10 left Simonovic just those couple of bucks short of what he needed to catch Trommer.
The two players to score in the 80s—David “Bleu Blanc Et” Ruge and James Politano were the two to emerge with $1,500 entries in Sunday’s Horse Player World Series entry-only play-in.
Bonus points, redeemable at any Montgomery Ward store, go to Politano for finishing fourth with his other entry.
Sunday’s $1,000 Guaranteed Exacta Tourney had the same winner for the second consecutive week.
Frank Fosbre did it completely differently this week, however. Last week, he was leading heading into the last race, hit a monster exacta in the finale, and wound up with a score five times greater than that of his nearest competitor. This week, he had two winners to eke out a victory by just $5.55. His big tally came in the 7th at Keeneland when he hit for $95.20. A winning exacta in Keeneland’s 9th then sent Fosbre over the top, putting to rest any concerns of a “Fosbre Flop”. The Exacta specialist this week earned $1,006 from a final purse of $1,438.
Gerald Hilton enjoyed his stay in our $8 Pick Six Jackpot tourney.
He had two winners to take top honors (Hilton Honors?). Since no one picked six, the Jackpot next week will be up to $3,241 for anyone able to go six-for-six.
There were two more BCBC qualifiers at HorsePlayers on Sunday as the big weekend draws closer and closer.
Steve Arrison (4 wins & 2 places) caught a $21.60 place collection in the last at Woodbine to get up and win one of the two available $10,000 entries in Sunday’s Low Ratio qualifier. “Battlin’” William Smith got the other thanks to three winners in a row in races 5 through 7 plus two runners up.
The other BCBC qualifier at HorsePlayers on Sunday was a Super Low Ratio Pick & Pray.
Sammy Richman had three winners (led by Latest Version—$32.00, $15.40—in the 6th at Keeneland) to finish first. All his scoring was done over the first five tourney races.
Alexa Zepp won a feeder on Saturday, then completed the two-step process by finishing second on Sunday to grab the other available prize. So you could say that last weekend, Zepp was buying a “Stairway to…the BCBC”.
After winning the feeder “Lex Zep” allowed herself a moment to daydream about getting to the BCBC…and about what headgear she might wear to it.
All of her lids appear to be lightweight…which is a good thing in case she needs to rush to the windows to get a play in right before post time. Perhaps her theme song at the BCBC will be the melodious “Hats Off to (Roy) Harper” from the Led Zeppelin III album. Or perhaps not. In any event, she’s “Going to California”.
In closing, we want to recognize a couple of excellent handicappers—and two of the many very nice people on the contest scene: Cara Yarusso, who captured last weekend’s Orleans Fall Classic as one of 87 (up from 60 last year) HorseTourneys qualifiers at the event…and Kenny Peck, who bested 116 others on Sunday in the NHC qualifier at Monmouth Park. Congratulations on your great victories!
This entry was posted in Uncategorized by ericwing. Bookmark the permalink.
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The quick and the dead, or 6 things that change when your service goes live
mattedgar introspection September 15, 2016 September 16, 2016 6 Minutes
Some of the organisations I work with are just starting out on this digital transformation thing. More and more of them, however, have been at it for quite some time. After 2, 3, even 4 years, a delivery process of discovery, alpha and beta is well embedded, in parts of the organisation at least.
Now I’m seeing more of the next struggle. I think it feels hard because, while alpha and beta can be treated as phases of service development, being live affects the whole organisation. This post is a first go at answering an existential challenge for digital specialists: what does it mean to go live?
1. It’s… alive!
No metaphor is wholly adequate. But it’s fair to say that accounts of organisational life have shifted over the last decades from the mechanical analogies of Taylorism to natural and biological ones. There’s less talk of levers and gears, more of evolution and growth.
What these analogies capture, and the machine-age ones miss, is the sense of aliveness. “Going live”, like Frankenstein’s monster, means crossing a threshold from being a well-assembled collection of parts to a sensing, thinking, adapting being in its environment.
There’s a quiet focus that comes from seeing serious numbers of people accessing your service right now. Digital teams make user activity visible. They fight hard to stay together for their service after crossing into live.
As Kit Collingwood-Richardson puts it, going live is like having a baby, with a whole future of parenting stretching ahead. “Go live is the start”.
My stickers for @racheljanewoods (will send extras for others) @KateBruckshaw @lolylena & whoever else wants them. pic.twitter.com/AcfPc2ZyFw
— Kit Collingwood (@kitterati) February 5, 2016
2. Time in reverse
In big organisations, agile development teams and service operations teams can sometimes feel like they’re on different planets. But I reckon they have something important in common: a healthy focus on the here-and-now. As Mat Wall says, agile is basically: “What do you want by Friday? And how can we make it better than last week?” Both those questions would be familiar in any high-performing front line service team. In a live organisation this common focus for development and operations becomes a powerful unity of purpose.
Agile development and operations both occupy what the sociologist Anthony Giddens describes as the temporal existence of “durée” – performing routinely, but with the possibility of change in every repetition. To Giddens, this is only the first of three sorts of time:
durée of day-to-day experience
life span of the individual
longue durée of institutions
The middle layer – the life span of the individual – is “irreversible time”. Its arrow goes in only one direction, and I have the grey hairs to prove it. This is where we find dedicated change management, the top-left to bottom-right sweep of the Gantt chart.
In contrast, the day-to-day and institutional time – a commitment stretching out indefinitely – are “reversible”. They always have the possibility to do over, to do differently, to do better.
To go live is to adopt a different attitude to time. We’re no longer burning down towards a deadline. We have embraced changefulness as a daily habit, supported by a long-term structure. We are committed to be here every day, as long as it takes, as long as there are people to be served. Any service that lacks this habit and structure isn’t live, it’s dead already.
3. Discovery is a culture, not a phase
Service lifecycle – Government Service Design Manual
Despite the recycling symbols, the service lifecycle drawn left-to-right can look a bit, well, waterfall-y. Discovery leads to alpha, as alpha leads to beta, and beta leads to live in resolutely irreversible time.
In particular, the distance between discovery and live seems to me wholly misleading. After all, live, running service affords all sorts of discovery possibilities that wouldn’t otherwise exist.
I know I’m not the only one who has tried redrawing this picture. I’ve tried drawing it as a stacked bar chart, as a circle, as a Möbius strip, and I’ve ended up with this…
In a sufficiently advanced organisation, discovery is a culture, not a phase. Intertwined live service and discovery continually fulfil and refine the purpose of the organisation.
Curious about something that’s showing up in the web analytics? Go and do some user research!
Hearing something new from customers in research? Go and see for yourself what is happening on the front line!
The odd ones out in this picture are alphas and beta – the phases where early-stage digital transformation organisations probably spend most of their time and attention.
Don’t think of (capital “D”) Discovery as something we do to prepare for the (definite article) Alpha Phase, think of an alpha version as one potential response to a new discovery. Alphas and betas are just tactical things we can make to bridge discoveries back into live service.
4. The strategy is (continuous) delivery
The discovery|live duality respects no boundaries between strategy, “change” and operations. Instead of clumsily executing planned but discontinuous change, the live organisation is always sensing and responding, making work visible, and reflecting frequently on how to do better.
Going live demands, in the words of David Marquet, that we move the authority to where the information is:
Policy advisors, strategists and designers can accomplish their work more effectively and at greater pace because they have very frequent contact with the realities of everyday service delivery
Everyone who delivers service has the power to make better decisions, multiple times per day; they must be trusted to take decisions that are aligned to the organisation’s purpose and priorities
Process changes are no longer pushed to workers on the front line; instead they frequently pull in change based on the demands they experience in contact with customers
Colleagues, suppliers and customers work together in a spirit of productive informality
Everyone becomes – to a greater or lesser degree – a service designer.
This is what I meant when I said learning by doing was the last target operating model you’d ever need.
5. All users become co-creators
Going live is often seen as only affecting the people inside an organisation. After all, users shouldn’t have to care what labels we use internally. Nevertheless, it should feel different to be a user of a live organisation.
Sure, your digital team may be highly user-centric already. You frequently engage users in defined, intentional activities – research visits, usability studies, private beta versions and so on. But to the majority of users, big organisations still appear unfeeling, inert and unresponsive.
When service is genuinely live, every interaction with users is an opportunity for new learning. Because the organisation is alive, it can sense people’s needs and adapt itself to meet them. Users become everyday co-creators of service. They learn to be more demanding, and to expect frequent change.
That’s when the fun really starts: when users realise that service can adapt to fit them. They begin to bring more than just their needs. They bring their unique capabilities to be combined with emergent competencies of the organisation. The “so that” line in the user story template comes into its own. We lift our sights from a deficit-based view of user needs to an asset-based vision of human potential. In live service, customer relationships are an endless source of ideas and innovation.
6. The new high score
Arbitrary double standards between capital and operational spending can easily bend organisational priorities out of shape. Agile abhors upfront spending divorced in time from actual customer value. Yet this is precisely what common accounting conventions reward. We need to change the high score.
Ironically the knowledge organisation’s most valuable assets are often its least visible. The conscious competence learning model presents “unconscious competence” as the apex of a pyramid of skill. Having begun in blissful ignorance, learners first become conscious of their own incompetence. They must go through a stage of consciously improving their competence until it comes so naturally that they can do it without noticing. But if we don’t notice the stuff we’re best at, there’s a risk we’ll undervalue it.
So the live organisation needs a new kind of balance sheet, one that deprecates unnecessary inventory and investments. Instead it recognises its most valuable asset: the growing skills, knowledge, networks and confidence of customers, workers and suppliers alike.
Live is when real digital transformation begins. It marks a radically different way of managing everyday work, and a new culture of continuous discovery. It will flatten decision-making structures, and transform passive users into active co-creators. The ways we measure and account for success will be different. But the potential payoffs are huge.
Go live. I dare you.
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3 thoughts on “The quick and the dead, or 6 things that change when your service goes live”
Matt Rayner (@attackbot) says:
I really like your DNA disco diagram – it is a big improvement on the standard view. There is still one thing implied though that I find quite insidious: not all discoveries should lead to a live release. What if you do the discovery to test the idea you had, and discover it was illusory and not worth acting on, or that it was actually a terrible idea and the user research indicated it would only make things worse? I have the same problem at the alpha ‘stage’ – how often do teams think that to not take a ‘prototype’ into beta is a sign of failure? I’ve seen perfectly good *prototypes* that proved the way everyone _thought_ a project should go was plain wrong and needed a different approach be swept under the carpet – rather than be celebrated and learnt from by the wider organisation. I guess I am arguing that those diagrams need dead-ends.
Thanks Matt, I like the idea about dead ends. Maybe there’s a drawing of this that branches out like a tree. The path we choose for a service is only one – and maybe not even the best – possible future.
Pingback: Worlds colliding – reflections 2 years into my work at NHS Digital – Matt Edgar writes here
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An Update from the RHS LGBT+ Working Group
June 24, 2019 royalhistsoc Equality Reports, RHS Policy and Advocacy Work Leave a comment
The RHS values the diversity of the historical community in all its forms and over the past several years has invested serious resources in projects that promote equality and inclusion. We believe that valuing diversity means listening to the voices, and respecting the experiences, of people whose lives and identities may be different to our own. This includes trans and non-binary people.
As historians, we know that ideas of sex and gender are complex and contingent, varying across time and space. Exploring that complexity through respectful dialogue can be a productive and intellectually stimulating exercise that furthers understanding.
However, ‘respectful dialogue’ cannot take place if we fail to acknowledge, and thereby exclude, our trans and non-binary colleagues and students’ identities. We reject as unfounded, claims that posit inclusion and respect as in opposition to academic freedom.
The RHS has established a working group to explore the research, teaching and dissemination of LGBT+ histories, as well as the experience of LGBT+ historians.
A preliminary survey inviting feedback on these topics will go live shortly and we will report early in 2020. We encourage all historians to engage with our work over the coming months.
Royal Historical Society LGBT+ Working Group
Professor Margot Finn, President of the Royal Historical Society, adds:
Since 2014-15, the RHS has completed three major surveys and reports on equality and inequality in UK university History, focusing on gender, race and ethnicity. These initiatives reflect both our commitment to equality, diversity and inclusion (EDI) and our knowledge that only by undertaking systematic research–rather than relying on presumed common knowledge–can we identify and address equality deficits. The LGBT+ Working Group has now been researching and discussing questions of EDI on behalf of historians for several months. I am very grateful indeed to them for their generosity, collegiality and insights on LGBT+ experiences in History. Their work is contributing significantly to the Society’s ability to promote excellent History teaching, supervision and research and to enhance the conditions in which historians work.”
Margot Finn
equalityLGBT+surveyworking groups
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Targeting G Protein–Coupled Receptors with Biologics for Therapeutic Use, Part 1
by Markus Koglin and Catherine J. Hutchings Sunday, June 1, 2014 12:07 am
G -protein coupled receptors (GPCRs) represent a target superfamily linked to many disorders across all therapeutic areas. Although this target class has been historically treated by small molecules and peptides, antibodies can offer a number of advantages over such molecules by virtue of their specificity, dosing frequency, and restricted penetration. They also can provide other functional effects specifically mediated by the Fc region (ADCC and CDC) as well as different modalities such as those offered by bispecific and antibody drug conjugates.
&bgr;1 AR Crystal structure depicting ECL2 in yellow
Similarly, a longer half-life in some instances (such as by FcRn-mediated recycling) can provide a therapeutic index that is more desirable than that of small molecules and peptides. In addition, antibodies can offer more diversity in pharmacological effects than provided by small molecules and peptides. This is because of the different nature of their extracellular interaction with a receptor compared with the interactions seen with small molecules and peptides, which often involve parts of the helices buried within the transmembrane regions..
Product Focus: Antibodies, GPCRs
Process Focus: Production, engineering, discovery
Who Should Read: Product development, analytical, clinical
Keywords: Stabilized receptors, phage display, expression systems, genetic engineering
However, the development of antibodies targeting GPCRs has lagged significantly behind antibodies for other drug target classes. The key challenge has been generation of sufficient stable GPCR antigens and immunogens that maintain the integrity of physiologically relevant epitopes. No robust or reproducible approach has been identified for either in vitro or in vivo methods. Binders are often obtained but not functional. Thus, sporadic success to date has been achieved only with receptors that have a higher than average stability and/or larger N terminal domains, such as subgroups of peptide receptors. The main issue to contend with is that GPCRs have a restricted extracellular surface where epitopes can be ligand sensitive (e.g., through binding that causes conformational changes in the receptor) and easily masked by long-chain detergents or lipids used for stabilization of purified receptors.
Here we summarize advances made in new approaches developed to address the challenges of antigen generation. We also review the antibody and biologics pipeline, with progress in the antibody space highlighted by some further interesting case studies. In Part 2, in BPI’s September issue, we review other biologics that have been evaluated or are in ongoing development for their use in targeting this important drug class of GPCRs
Enabling Technologies to Generate New Antigen Formats
We previously reviewed commonly used approaches to generate GPCR antigens (1). Although antibodies can be raised successfully and blocking antibodies have been described for a number of GPCRs (2), the success rate in delivering pharmacologically active antibodies is low. To provide correctly folded epitopes of extracellular domains or extracellular loops of GPCRs, presenting the receptor of choice embedded in membranes can
yield antibodies that recognize a biologically relevant conformation of the receptor (3).
That approach, however, generates a large pool of off-target antibodies and requires extensive screening. Another drawback is low expression levels — even in cells that over-express the target (e.g., by transfection technologies). However, a number of alternative emerging technologies are being implemented in monoclonal antibody (MAb) discovery for targeting multispanning membrane proteins. We describe a number of such examples below.
Novel Expression Host System: Tetragenetics has developed a system that could prove useful as an alternative for providing antigens in the form of whole cells or membrane vesicles for generating functional antibodies. The company applies Tetrahymena thermophilia to the over-expression of difficult-to-express membrane proteins (Tetraexpress technology). This technology can be used to formulate different formats of antigen preparations such as membranes, vesicles, and even soluble purified protein. The host system has been applied specifically to the cell-surface expression platform for ion channels (SionX technology). Tetrahymena is an interesting expression host for recombinant membrane proteins: It provides a large surface area and uses a significant proportion of its metabolism to produce membrane proteins. Therefore, the system can enable high-density expression of recombinant membrane proteins on the cell surface. Studies have shown that the target protein comprises up to 5% of the protein content in prepared membrane vesicles (4). This host system also is applicable for expression of GPCRs (personal communication).
Virus-like particles (VLPs) continue to show utility. For example, their incorporation into phage display selection strategies generated anti- CXCR2 MAbs that mediated efficient antibody-dependent cell cytoxicity and complement-dependent cell killing of CXCR2 over-expressing Chinese hamster ovary (CHO) cells using human serum with almost 100% cell death and IC50 values in the low nanomolar range (5). Effects of that study were specific for CXCR2- expressing cells. Also, a number of commercial efforts have been established that use liposomes (Integral Molecular), cell-free expression for the generation of proteoliposomes (Synthelis), and magnetic proteoliposomes (MSM Protein Technologies) in GPCR-MAb discovery.
Denatured GPCRs: The ideal antigen for therapeutic antibody drug discovery is correctly folded, purified protein. The purification of good quality membrane protein is still a very challenging field. For GPCRs, it is still very difficult to achieve milligram quantities of suitable antigen material. Researchers have described using denatured GPCRs as immunogens to raise highly specific antibodies (6). Although the generated antibodies appear to be specific and were able to show a positive response in cytofluorometric analysis, no functional data of these antibodies were presented. One disadvantage of this approach is that many GPCR epitopes in the native folded receptor will not be correctly preserved, thereby altering the diversity of the resulting antibodies.
Other research groups have used the advantage of the large soluble extracellular domains of some GPCRs to raise active antibodies. Those researchers implemented the extracellular domain of the glucagon receptor to generate MAbs that demonstrate in vivo activity (7). The human MAbs NPB112 effectively lowered glucose levels in diabetic animal models with mild and reversible hyperglucagonemia. Mice treated with NPB112 showed a significant improvement in the ability of insulin to suppress hepatic glucose production, so it might be a promising therapeutic modality for treatment of type 2 diabetes.
A different research group describe two antibodies (MAb1 and MAb23), where MAb1 inhibited the glucagon receptor by occluding a surface extending across the entire ligand cleft (8). The second antibody, MAb23, blocked glucagon binding and inhibited basal receptor activity indicating an inverse agonistic behavior.
Liposomes: Although purified GPCR protein can be unstable even when embedded in detergent micelles, reconstitution of the purified material into liposomes (which may include additional lipids and cholesterol) can provide purified receptor in a more stable format. Those additions result in an increased micelle size that can restrict the access of antibodies to GPCR epitopes. A few groups have published studies on functionally active antibodies raised from purified GPCRs. One publication describes generation of specific antibodies (by in vivo immunization using liposome-embedded adenosine A2A receptors) that recognize conformational epitopes (9). The Fab fragment of a functional antibody — which completely inhibited agonist binding — was used for cocrystallization. Structural analysis suggests that the receptor was locked into an inactive conformation by tight binding of the antibody to an intracellular domain of the receptor.
Studies focused on &bgr;
-adrenergic receptor (&bgr;2AR) have identified a camelid nanobody (Nb80) with G-protein-like behavior. To generate receptor-specific nanobodies, a llama was immunized with purified agonist-bound &bgr;2AR reconstituted at high density into phospholipid vesicles (10). Nb80 was then used as starting point to construct a library of mutants in which residues at the receptor-binding surface were randomized with conservative substitutions (11). The library was displayed on the surface of a yeast strain and subjected to a number of selection rounds using purified biotinylated &bgr;2AR. This process identified a nanobody (Nb6B9) that bound to the agonist conformation of the receptor (BI167107 ligand-occupied receptor) with affinities of 6.4 nM resulting in a 2.8 Å crystal structure complex of agonist–receptor–nanobody. However, this approach has been applied only to the creation of tools for cocrystallization. These antibodies are not suitable as therapeutics because they primarily target intracellular domains of the receptor.
Our group is now leveraging the Heptares StaR approach to generate antigens for GPCR antibody drug discovery, which has been exemplified by a proof-of-concept study based on the &bgr;1-adrenergic (&bgr;1AR) receptor (12). Although it has been postulated that a detergent-purified receptor is not a suitable agent for in vivo immunization because of detergent dissociation and subsequent receptor misfolding, we were able to obtain agonist MAbs against &bgr;1AR that recognized different epitopes on the receptor.
We designed &bgr;1AR StaR and used it as antigen (both DNA and protein) for in vivo immunization and subsequent hybridoma generation. Those MAbs enabled receptor signaling through G proteins in the absence of &bgr;-arrestin recruitment, indicating the potential for StaR proteins to elicit antibodies with highly selective pharmacology. The creation of a StaR allows purification in shorter chain detergents, thereby exposing larger receptor surface areas for antigen–antibody interaction. Increased receptor stability further improves receptor performance using in vivo immunization technologies. StaR proteins also are amenable to in vitro display platforms. A number of purified StaR antigens are being used in phage antibody library selection processes through a number of collaborations (unpublished data).
Monoclonal Antibodies Against GPCRs
By the end of 2012, 37 therapeutic antibodies had been approved and marketed around the world, generating sales of $64.5 billion in 2012 (13). Of the 10 best-selling drugs that year, six were MAbs, each with annual sales exceeding $5 billion. So far, however, only one GPCR-targeting antibody has been approved (Poteligeo mogamulizumab, an anti-CCR4 antibody approved in Japan), which reflects this central technical challenge of accessing reliable high-quality GPCR antigen.
We have published a review outlining case studies of antibodies currently in the clinic that target GPCRs — notably CCR5, CXCR4, CCR2, C5aR, and CCR4 (1). Based on information available through company websites, Thomson Pharma database, clinicaltrials.gov, and other sources, we summarized an updated overview of examples of MAbs currently in development (
Table 1), as well as identified further interesting case studies, as below.
Table 1: Examples of GPCR MAbs currently in development (NDRR = No development reported recently)
Anti-Bradykinin2 (DM-204) is a MAb targeting the bradykinin 2 receptor, which displays agonist behavior (14). Agonist antibodies are highly desired and considered to be very difficult to achieve. They offer several advantages over shorter-acting peptides or small molecules. DM-204 is a novel MAb to treat Type 2 diabetes (T2D) and some of its associated complications. In an independently conducted study, chronic administration of DM-204 prevented disease progression within an in vivo T2D model (www.diamedica.com/Product_Pipeline/dm-204). Treatment with DM-204 resulted in statistically significant lower HbA1c levels, fasting blood glucose levels, systolic blood-pressure levels, and total cholesterol levels — all of which are important factors in T2D disease management. Reduction in HbA1c is the critical endpoint measurement for regulatory approval relating to a T2D medication. In addition, about 70% of Type 2 diabetics are prescribed antihypertensive medications to control blood pressure and prevent heart disease and stroke. It follows that the antihypertensive and cholesterol-lowering ability of DM-204 may significantly reduce the need for such medication and protect from heart disease and stroke complications in T2D.
Anti-protease activated receptor (PAR2) belongs to a family of GPCRs that are activated upon proteolytic cleavage of the N terminus of the receptor, thereby activating the receptor signal cascade. So far, transgenic mouse studies have associated PAR2 activation with inflammation, pulmonary hypertension, and other pathophysiological conditions (15).
The role of PAR2 in inflammation continues to be investigated. PAR2 activation has been described as protective rather than proinflammatory such as in airway disorders (16). The current understanding is that some functions of PAR2 may indeed be protective in response to endogenous proteases, whereas others are detrimental and promote disease progression.
A small panel of PAR2 antibodies are commercially available, but only a few selective ones have shown in vivo effects. SAM11 is the most commonly used antibody (MAb IgG2a raised against N-terminal residues 37–50) and has recently demonstrated in vivo efficacy by attenuating collagen-induced arthritis in mice (17). In one study, researchers reported a panel of PAR2 antibodies that demonstrated good binding affinity to PAR2 with dissociation constants as low as 100 pM (18). Those fully human antibodies, identified through the HuCAL GOLD phage display library using a peptide-derived from the N-terminal region of human PAR2, bound to the N terminus of the receptor and thereby prevented proteolytic cleavage and activation of the receptor. The affinity-maturated IgG4 antibodies 2B and 2D were able to inhibit trypsin-induced intracellular calcium release, cytokine secretion, and relaxation of rat aortic rings (18). The antibodies also showed inhibition of the inflammatory swelling response in a mouse model of inflammation. Further antibodies have been described in patents by Amgen (US20130189281) and Regeneron (US20110059095), but to our knowledge none of those antibodies have entered clinical validation.
Anti-S1P3 (7H9): Sphingosine 1-phosphate (S1P) is a lipid-signalling molecule. It is generated by the phosphorylation of sphingosine by sphingosine kinase. Most of its effects are mediated by a family of five receptors (S1P1-5R). Effects mediated by S1P include proliferation, survival, and cytoskeletal rearrangement (19). Some studies have also indicated a protumorigenic role of S1P correlating with increased proliferation and cell survival (20).
Involvement in the processes of angiogenesis highlights the importance of this pathway in cancer progression (21). Neutralization of S1P has a potent tumor-suppressive effect (22). The effects in breast cancer cells are largely mediated by activation of S1P3 (23). S1P3 receptor also has been shown to mediate proinflammatory responses in a number of physiological conditions (24). Specific antagonism could provide effective protection against the progression of certain cancer types or types of inflammation. A recent publication characterizes a MAb, 7H9, against the S1P3 receptor (25). The antibody was raised by immunizing mice with S1P3 peptide. Immunocytochemistry confirmed specificity for S1P3 receptor, and 7H9 was able to inhibit S1P3-mediated arrestin translocation and receptor internalization. 7H9 showed clear inhibition of S1P-mediated calcium response in RH7777 transfected cells and partially inhibited the Gi coupled cAMP response of S1P. Furthermore, 7H9 ameliorates systemic inflammation in mice after LPS challenge. The MAb also inhibited development of breast tumor xenografts in mice with a fourfold increase in necrotic regions of the 7H9-treated tumors. Further developments will demonstrate whether such an antagonistic antibody against the S1P3 receptor will be beneficial and clinically relevant.
Anti-CGRP-R (AMG-334): Migraine is the most prevalent of neurological disorders and can affect patients throughout their lifetime. CGRP and its receptors are largely expressed in neurons and glia, both centrally and peripherally. Peripheral actions of CGRP appear to involve neurovascular inflammation, which is an important factor for migraine (26). CGRP effects in the brainstem also have a key role in the pathophysiology of migraine by resulting in neurogenic inflammation (27). Therefore, CGRP is involved in the pathophysiology of migraine both centrally and peripherally (28). Pain improvement can be achieved by antagonism in the periphery, the center, or both. Brain penetration may not be essential for analgesic properties of such antagonists.
Effects of one of the most potent endogenous vasodilators have been extensively described for CGRP. Based on its physiological role, however, some concerns have been raised regarding CGRP receptor (CGRP-R) inhibition (29). Concerns that CGRP-R antagonists cause vasoconstriction (thereby presenting cardiovascular safety risks) have so far not been confirmed. In vitro and in vivo studies have repeatedly shown that CGRP-R antagonists (small molecules and antibodies) do not have vasoconstrictor activity on coronary arteries (30). The first CGRP-R antagonist to be tested in humans (olcegepant) showed no effects on systemic hemodynamics (31). Therefore, cardiovascular safety concerns regarding CGRP-R antagonists have yet to be elucidated, but additional data are required.
Four distinct small-molecule CGRP-R antagonists have demonstrated proof of efficacy, but all were discontinued for a number of reasons (29). Currently, two small molecules are in clinical trials (NCT01445067 and NCT01613248). Because small-molecule CGRP-R antagonists have failed to reach commercialization, free CGRP and CGRP receptors have both been targeted using MAbs that can bind and neutralize biological activity (32).
Three MAbs against the CGRP peptide ligand are currently in clinical trials: LY2951742 (Eli Lilly), ALD403 (Alder Biopharmaceuticals), and LBR-101/PF0442g7429 (Labrys Biologicals). But only one MAb is targeting the CGRP receptor (AMG- 334). Amgen is developing AMG-334 for prevention of episodic migraine where AMG-334 (a human MAb) inhibits the receptor. Two phase 1b studies are testing the safety and pharmacokinetic (PK) profile of single- and multiple-ascending doses in healthy volunteers and in individuals with migraine. In summer 2013, a phase 1 study focusing on single-dose administration was terminated, but the parallel multiple-dose approach is currently ongoing (NCT01723514). This antibody has since progressed to phase 2 clinical trials to evaluate its efficacy and safety in migraine prevention (NCT01952574) and will be compared with placebo on the change from baseline in monthly migraine days. A second indication for AMG- 334 also has been submitted to a phase 1 study for assessment in women with hot flushes associated with menopause (NCT01890109).
Anti-CCR4 Mogamulizumab: We previously described the status of a defucosylated humanized IgG1 antagonist derived from the POTELLIGENT platform, a technology to produce antibodies with enhanced ADCC activity (developed exclusively by Kyowa Hakko Kirin) (1). In 2012, mogamulizumab was approved in Japan for treatment of relapsed or refractory adult T-cell leukemia-lymphoma (ATL). It is currently the first and only anti-GPCR antibody that has received marketing approval under the name Poteligeo as an injection therapy. Phase 2 development is currently ongoing for adult T-cell leukemia-lymphoma (ATL) and cutaneous T-cell lymphoma in the United States and for peripheral T-cell lymphoma in the United States and Europe. Further clinical trials have been initiated and are currently listed as in recruiting stage (clinical trials.gov). Recent published case studies describe some adverse effects during the treatment with mogamulizumab. Diffuse panbronchiolitis has been described during a therapy for relapsed adult T-cell leukemia and/or lymphoma (33). The intent is to raise awareness of this complication and the possible development of such autoimmune diseases that arise most likely as a consequence of targeting T-regulatory cells that express CCR4.
Another case study reported development of Stevens-Johnson Syndrome (SJS) during mogamulizumab treatment (34). Further clinical trials and the broader use of mogamulizumab will shed more light on the frequency of rare side effects in the future.
Ahead in Part Two
In BPI’s September issue, the second part of this article reviews other biologics — such as peptides and alternative scaffolds — that have been evaluated or are in ongoing development for their use in targeting this important drug class of GPCRs.
Markus Koglin, PhD, is associate director, protein engineering; and corresponding author Catherine J. Hutchings is principal scientist, antibody alliance management and strategic partnering, at Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, Herts AL7 3AX; 44-1707358698; fax 44-1707358640; cath.hutchings@heptares.com. The HEPTARES name, the logo, and STAR are trademarks of Heptares Therapeutics Ltd.
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17.) Crilly, A. 2012. Immunomodulatory Role of Proteinase-Activated Receptor-2. Ann. Rheum. Dis. 71(9):1559-1566
18.) Giblin, P.2011. Fully Human Antibodies Against the Protease-Activated Receptor-2 (PAR-2) with Anti-Inflammatory Activity. Human Antibodies. 20(3-4):83-94
19.) Choi, JW. 2010. LPA Receptors: Subtypes and Biological Actions. Ann. Rev. Pharmacol. Toxicol. 50:157-186
20.) Sarkar, S. 2005. Sphingosine Kinase 1 is Required for Migration, Proliferation, and Survival of MCF-7 Human Breast Cancer Cells. FEBS Lett. 579(24):5313-5317
21.) Skoura, A. 2007. Essential Role of Sphingosine 1-Phosphate Receptor 2 in Pathological Angiogenesis of the Mouse Retina. J. Clin. Invest. 117:2506-2516
22.) Visentin, B. 2006. Validation of an Anti- Aphingosine-1-Phosphate Antibody as a Potential Therapeutic in Reducing Growth, Invasion, and Angiogenesis in Multiple Tumor Lineages. Cancer Cell. 9(3)225-238
23.) Watson, C. 2010. High Expression of Sphingosine 1-Phosphate Receptors, S1P1 and S1P3, Sphingosine Kinase 1, and Extracellular Signal-Regulated Kinase-1/2 is Associated with Development of Tamoxifen Resistance in Estrogen Receptor-Positive Breast Cancer Patients. Am. J. Pathol. 177(5):2205-2215
24.) Nixon, GF. 2009. Sphingolipids in Inflammation: Pathological Implications and Potential Therapeutic Targets. Br. J. Pharm. 158(4):982-993
25.) Harris, GL. 2012. In Vitro and In Vivo Antagonism of a G-Protein-Coupled Receptor (S1P3) with a Novel Blocking Monoclonal Antibody. PLOS One. 7:e35129
26.) Radant, AC and Russo, AF. 2011. Calcitonin Gene-Related Peptide in Migraine: Intersection of Peripheral Inflammation and Central Modulation. Expert Rev. Mol. Med. 13:e36
27.) Williamson, DJ and Hargreaves, RJ. 2011. Neurogenic Inflammation in the Context of Migraine. Microsc. Res. Tech. 53(3):167-178
28.) Ho, TW, Edvinsson, L,and Goadsby, PJ. 2010. cGRP and Its Receptors Provide New Insights into the Migraine Pathophysiology. Nat. Rev. Neurol 6(10):573-582
29.) Bigal, ME, Walter, S, and Rapoport, AM. 2013. Calcitonin Gene-Related Peptide (CGRP) and Migraine: Current Understanding and State of Development. Headache. 53(8)1230-1244
30.) Chan, KY. 2010. Characterisation of the Calcitonin Gene-Related Peptide Receptor Antagonist Telcagepant (MK-0974) in Human Isolated Coronary Artieries. J. Pharmacol. Exp. Ther. 334(3):746-752
31.) Peterson, KA. 2005. The CGRP Antagonist, BIBN4096BS Does Not Affect Cerebral or Systemic Haemodynamics in Healthy Volunteers. Cephalalgia. 25(2):139-147
32.) Silberstein, SD. 2013. Emerging Target-Based Paradigms to Prevent and Treat Migraine. Clin. Pharmacol. Ther. 93(1):78-85
33.) Kato, K. 2013. Diffuse Panbronchiolitis After Humanized Anti-CCR4 Monoclonal Antibody Therapy for Relapsed Adult T-Cell Leukemia/Lymphoma. Int. J. Hematol. 97(3):430-432
34.) Ishida, T. 2013. Stevens-Johnson Syndrome Associated with Mogamulizumab Treatment of Adult T-Cell Leukemia/ Lymphoma. Cancer Sci. 104(5):647-650
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← Kirby’s dilemma
No joke →
When the rabbit’s foot deserts you
This is harsh.
There’s a real chance that Gus Malzahn, who enters the season on the hot seat, doesn’t make it out of September with his job. That’s because there’s a real chance that the Tigers, who open the season with four home games, start 0-4 on the year against Clemson, Arkansas State, Texas A&M, and LSU. Yes, Arkansas State, a team that is exponentially better than the Jacksonville State team that almost beat Auburn on the Plains last year. What issues appear solved heading into the season? The defense, outside of Carl Lawson, isn’t noticeably improved, and the quarterback situation is anything but settled — they’ll either roll with Sean White again or go with John Franklin III instead of Jeremy Johnson. Franklin, a junior college transfer, left Florida State because he wasn’t deemed good enough to be the fourth-string QB. They also have only one running back with collegiate experience and lost their two leading receivers from 2015. The makings of a bounce back do not appear to be in place — there’s a real chance Auburn finishes in last place in the SEC West again in 2016.
Dayum. Even I’m not that down on Auburn’s chances this season — although I reserve the right to change my mind if Lawson goes down again.
Filed under Auburn's Cast of Thousands
78 responses to “When the rabbit’s foot deserts you”
You must realize that many of us are enjoying the anticipation of Auburn sucking. I can only hope the season plays out as gloomy for them as some think it will. I hope my ill will toward them doesn’t bite me in the karma.
Got Cowdog
It’s not ill will. It’s Karma having it’s way with ’em.1986 baby!
86? How about ’05, ’10 and ’13?
Yeah! Those too! But this one stands out, some of my classmates were there.
I heard after they beat Bama there were shirts at Auburn that said “The strong we hose. The weak we beat.” That was the first Auburn game I’d missed in a while.
I think it was the next time we went down there that the game shirts for that game said “Nothing Stinks Like a Wet Dog”.
I really wish I had gotten one when I was in town–that was pretty funny.
“Those who spray must pay”
T-shirt the following year before the Auburn game. I believe we lost (perhaps not surprisingly).
I love that video.
Hated that game.
There is a lot of talent wandering around on the Plains. I’m not sure Gus knows how to use it though. He was an offensive genius with Cam Newton and Nick Marshall, but he seems to be struggling to put a serviceable unit on the field now.
Auburn losing to Arkansas State? I like the sound of that.
I’d certainly love it, BUT I am not holding my breath. Arkansas State is not capable of beating Auburn this year. I suppose it’s conceivable that they could start 1-3, but I don’t know that I anticipate A&M going into Jordan-Hare and getting that win, either. Home field is big, and Auburn’s got it in these games. I think they’ll be fine.
Reservoir Dawg
The dumpster fire continues. Even the laughing three-legged East Alabama jackrabbit is in flames. Burn, baby, burn.
Auburn did pretty well with cornerback at QB, so FSU’s fourth string cast off will probably do okay. I think they split September and November. The difference between 6-6 and 8-4 is what they do in October at MSU, vs Arkansas, at Ole Miss. I would be giddy pleasantly surprised if Auburn did a faceplant, though.
Franklin is fast, but he’s smaller than Marshall and doesn’t have nearly as strong an arm, either. Not to mention he hasn’t won the job yet.
Between the QB situation, a difficult schedule and being on the third DC in three seasons, I’m not convinced eight wins is doable.
Franklin split the QB job at a community college.
He had 38 completions in 70 attempts against community college competition.
He had 733 yards rushing in 9 games against community college competition.
Not exactly “man among boys” stats.
Did you see ‘Last Chance U’?
That kid can really really run the ball. He could also throw INT’s like Ramsey. The Coaches went with their version of Lambert as the starter for the season. QB1 is out of football and working on his degree at Miss State. QB2 might start for Auburn.
Life is funny like that.
(We should see Ollie in Sanford 09/10 this year if nothing has happened to him).
Yes – I watched Last Chance U and he really didn’t split the job with a guy who is no longer playing college football. He was beaten out by a guy who is no longer playing college football.
So being on a third coordinator, having a difficult schedule, and having an unsettled qb situation makes you convived 8 wins isn’t very doable. That does not bode well for Georgia then.
I would love to be wrong, but auburn has too much talent to lose 6 games. Their offensive line (from all the stud Georgia recruits they swiped in 2015) is going to be a lot better and the qb will benefit.
I think this is a classic case of Auburn defying expectations, which they do seemingly every year.
I’m not trying to be one, but have you looked at Auburn’s strength of schedule? To compare it with Georgia’s is a stretch.
I can’t argue against your point there – Auburn’s schedule is a nightmare. But you can make a case that a) Georgia has a plenty tough schedule (SEC + two Power 5), and b) has even the same problems listed above and lacks Auburn’s talent/depth on the lines.
I’m not picking Auburn to win the West, but I think they play Bama and LSU close, beat Ole Miss, lose to Clemson (too early on schedule) and may beat UGA. They’re def underrated right now and have WAY too much talent to be a 6-8 loss team.
All that said, I’d love nothing more in life than to be entirely wrong.
They have recruited on the level of Bama, LSU, UGA and Clemson…and all those teams are on the schedule. Plus A&M, Miss St., Ole Miss (who has recruited pretty well, too), and Arkansas. That’s 8 games that are very losable. They are lucky to get Vandy this year from the East.
Even Chuck Oliver is down on Auburn this year. Said their LB corps is Miss. State weak, no answer at QB, and the schedule is brutal.
Chuck Oliver continues to be around? I want to see his picks before I dip into the pool next week because the opposite of his picks will be the teams to select.
Have you been keeping up, dude? Too much talent to lose?
Would somebodyrefresh my memory, please? Didnt they lose 6 games like, last year? Lost 6 and damn near got beat by Jacksonville State!
And that was before they lost their best two RB’s, both of their top WR’s, and most of their O-line.
Too much talent?
Either keep up or wake up, because your perspective seems a bit fuzzy to me.
Your honest assessment isn’t taken as a downer. Your points are valid and maybe we should open our eyes more instead of making them as slits when discussing Auburn. Teams and fans can set themselves up when revenge is so close and one can taste it before every game with them. I certainly fall into that category.
What Athens Dog said^^^^^^.
I view Gus similarly to Paul Johnson in hoping they stay in their current roles forever. I love the sideline shots of Gus when he has run out of ideas beyond cranking his hand in the “hurry up” gesture.
I do not know why this is not mentioned more often, seriously he actually looks befuddled on the sidelines sometimes.
He even looks Huddle House befuddled – like he’s there because his wife doesn’t cook, but he’s afraid someone will find out.
With Gus, that has to be Waffle House
6claude
Agree with this. Hope they can find a silver lining in an otherwise mediocre season with a loss to the Dawgs.
Need Gus and Paul to hang around as long as possible.
Couldn’t happen to a nicer bunch of folks in my opinion. But remember when Auburn is suppose to be good they are bad and vice versa.
Agreed. Auburn seems to always swing pretty far against expectations so all this negative talk makes me nervous.
I’m thinking this year’s under hype is about as bad as last year’s over hype. 8-5 when everyone picked you to win the SEC is bad.
8-5 when everyone picks you to be fired before Halloween is good.
They have quality depth on the offensive and defensive line. Or should, based on recruiting metrics. That sets a pretty comfortable floor for this team, doesn’t it?
But they also have Rodney coaching the D-line which may negate the talent there. Good recruiter but seems way underachieving as a coach. Look at the players he coached who were midling players who hit the NFL as stars.
How many folks are they still paying that no longer work there? Can they actually afford to fire Gus?
The only thing better than an Auburn dumpster fire is a Gator dumpster fire. If only the Gods aligned and they both burn in the same season my life is good.
You might get your wish this season…
Santa, I have been really fucking good this year.
I still can’t believe they talked Derrick Brown and Kyle Davis into going there. Boggles the mind
The bagman visited …
If history is any indication, Garner will coach Derrick Brown to be invisible during his college career. That will be followed by Brown having a terrific nfl career and a bust in Canton, OH. Lawson is experiencing this now.
Don’t forget Montravius Adams. I think Greg Pyke just pancaked him again as I typed this.
I kind of think Malzahn is kind of a Neuheisel-ish coach. Decent on the xs and os, but could not care less about strength and all the other trenches stuff. Thinks he can always outscheme you.
They’ve recruited substantially Bette than us on the lines over the past 4 years.
You stirred my interest. I had to see for myself. Per Dawgs247 –
2016 Aub – DL (1)5star, (5)4star, (1)3star – OL (1)3star
2016 UGA – DL (4)4star, (1)3star – OL (1)4star, (2)3star
2015 Aub – DL (1)5star, (1)4star, (2)3star – OL (4)4star, (1)3star
2015 UGA – DL (1)5star, (5)4star, (2)3star – OL (1)4star, (3)3star
2014 Aub – DL (4)4star, (1)3star – OL (1)4star, (1)3star
2013 Aub – DL (2)5star, (2)4star – OL (2)3star
2013 UGA – (2)4star, (3)3star – OL (3)3star, (1)2star
Aub has done some better on DL but like us, they have not been world beaters on the OL recruiting.
P.S. I didn’t factor in those who didn’t pan out. I just looked at the commitments.
You do good work. If we want to know more, you left the door open and not appeased us, the ultra-lazy goofusses.
It’s fun to mock Auburn, but there is a significant portion of our fan base would would happily trade places with them so they could get those 3-4 extra games that they played in a couple of years ago.
Eh, they’ll end up being a middling team. They were in most of their losses last year, and MSU, Arkansas and Ole Miss should take a step backward. They are nowhere near a Western Division title, but they’ll probably end up 8-4 or 7-5 and 5-3 or 4-4 in the conference.
saildawg
If you have netflix, I urge you to watch Second Chance U. It profiles last season at East Mississippi JUCO. Not only is it very entertaining football documentary, it gives you a good idea of the type of player John Franklin III is. He is talented, but I came away very unimpressed with his mental approach to the game, and his general overall attitude. He never won the starting job, and seemed to struggle grasping the concepts of the offense. He is an excellent runner, if Gus can max out his running potential he could be successful. I get the feeling if he does not have early success he will mentally quit though.
I believe you mean Last Chance U. But thanks. It looks interesting.
Ah, that makes more sense.
I object to the use of “Second Chance U” to refer to any program other than Auburn. That aside, thank for the Netflix rec!
Yes that was what I was thinking as well!!
Second chance U= East Mississippi
Last Chance U= Auburn
Last Last Chance U= Auburn
Double Last Last chance U = Auburn
Art Briles approves of this post.
Sweeet.
Auburn being pounded into the dust.=Good Times. I live and work among them.
LamNURSE
The next coach at Auburn is…. Lane Kiffin
…Bobby Petrino.
DankJankins
Wow…watching Lane Kiffin at Auburn would be some serious entertainment. I thought the Bama/Barn rivalry could not get any more heated but putting Kiffin on the Barn side would make rival the pits of hell.
The trolling would make great blogger material.
That would be amusing to watch.
His Twitter account would melt down.
And Gus buzz claimed he was ready to name a starter, LOL.
I’d like to see them go 8-4 with losses to us, Bama, LSU and Ole Miss. That would be good enough for Gus to keep his job but not good enough to help their recruiting. We don’t need Gus leaving and them getting an actual good coach.
0-12 would be my choice…. 🙂
sers. The last year of cheese dick on the plains was a lot of fun. Love heading to an away game when the other team’s entire campus/stadium feels like they’ve been run over by a truck. twice.
Auburn sucks.
Still feel Clemson -7 against AU on the plains is the best bet of the opening weekend. Might as well build your stash for the season on that one. Other games scare me with so little known before one game played. I feel differently about these two teams, they are who we think they are (I hope.)
I like the under in the game, too. Think I heard 59.5 yesterday. Don’t think Auburn can score enough points to hit the over on that one. But yea, Clempson -7 seems like stealing.
Dunno how you write a paragraph about how Auburn is going to disappoint this year without mentioning Kevin Steele. If Malzahn gets fired, then the biggest reason will be his QB recruiting and then the second reason will be hiring Steele. The same was true for Richt, just replace Steele with Schottenheimer.
By the way, the author lost me with this sentence:
“The spot could easily belong to Michigan or Ohio State, as all three teams have the same problem — massive attrition — but Michigan State is the worst recruiter of the three elite teams, so Sparty is going to take the fall on this one.”
Michigan’s attrition consists of the QB, one offensive lineman, two fullbacks, one defensive end, two linebackers, and a safety. The reason why they’re picked so high this year is that they have a ton of talent coming back. Next year, they’ll have massive attrition because they’re starting 15 seniors this year and Peppers is likely to go pro.
How does Auburn get these ridiculous schedules? 8 home games, including 5 in a row to start the year?
4 non-conference games, all at home, and 4 home conference games. They don’t have 2 neutral site games like a certain team we know. Payback comes when they go on the road to Georgia and Alabama to close the season.
Somewhere there’s a 3-footed rabbit smiling.
And, in case some of you have forgotten, Aaron Murray owned their ass. He always outscored them, just as he did immediately before the immaculate reception – we needed a score with a minute and a half and he produced. He had nothing to do with what happened in the last tip drill gone awry. What a sweet memory we have of the revenge game the following year.
AU is not worthy of this blog.
Lane Kiffin at Auburn? Fantasy Dawgporn if ever there was any. Fun to think about. Could Kiffin snag a couple of Bama kids as graduate transfers? Saban-Kiffin throw down would be fun, no doubt.
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Primary care referrals of patients with potentially serious diseases to the emergency department or a quick diagnosis unit: a cross-sectional retrospective study
Xavier Bosch1,
Ona Escoda1,
David Nicolás1,
Emmanuel Coloma1,
Sara Fernández1,
Antonio Coca1 &
Alfonso López-Soto1
In Spain, primary healthcare (PHC) referrals for diagnostic procedures are subject to long waiting-times, and physicians and patients often use the emergency department (ED) as a shortcut. We aimed to determine whether patients evaluated at a hospital outpatient quick diagnosis unit (QDU) who were referred to ED from 12 PHC centers could have been directly referred to QDU, thus avoiding ED visits. As a secondary objective, we determined the proportion of QDU patients who might have been evaluated in a less rapid, non-QDU setting.
We carried out a cross-sectional retrospective cohort study of patients with potentially serious conditions attended by the QDU from December 2007 to December 2012. We established 2 groups of patients: 1) patients referred from PHC to QDU (PHC-QDU group) and 2) patients referred from PHC to ED, then to QDU (PHC-ED-QDU group). Two observers assessed the appropriateness/inappropriateness of each referral using a scoring system. The interobserver agreement was assessed by calculating the kappa index. Multivariate logistic regression analysis was performed to identify the factors associated with the dependent variable ‘ED referral’.
We evaluated 1186 PHC-QDU and 1004 PHC-ED-QDU patients and estimated that 93.1% of PHC-ED-QDU patients might have been directly referred to QDU. In contrast, 96% of PHC-QDU patients were found to be appropriately referred to QDU first. The agreement for PHC-QDU referrals (PHC-QDU group) was rated as excellent (ϰ = 0.81), while it was rated as good for PHC-ED referrals (PHC-ED-QDU group) (ϰ = 0.75). The mean waiting-time for the first QDU visit was longer in PHC-QDU (4.8 days) than in PHC-ED-QDU (2.6 days) patients (P = .001). On multivariate analysis, anemia (OR 2.87, 95% CI 1.49–4.55, P < .001), rectorrhagia (OR 2.18, 95% CI 1.10–3.77, P = .01) and febrile syndrome (OR 2.53, 95% CI 1.33-4.12, P = .002) were independent factors associated with ED referral. Nearly one-fifth of all QDU patients were found who might have been evaluated in a less rapid, non-QDU setting.
Most PHC-ED-QDU patients might have been directly referred to QDU from PHC, avoiding the inconvenience of the ED visit. A stricter definition of QDU evaluation criteria may be needed to improve and hasten PHC referrals.
Long waiting times and emergency department (ED) overcrowding are common in countries with public health systems, even when primary healthcare (PHC) systems are strong [1].
Over the last decade, the annual demand for ED care in Spain has grown by > 4% compared with a population rise of 2%, and has often surpassed the growth in ED capacity [2]. In Spain, around 30% of ED consultations are deemed inappropriate, and while some ED have attempted to improve efficiency by redesigning circuits, most of the resulting benefits are lost after a few years [2].
There is evidence that the referral process is often suboptimal, with the consequent impact on patients, costs and the system itself. However, despite inappropriate use, including cases better handled in PHC, not all PHC centers have the facilities and resources to diagnose and treat urgent cases needing same-day care, even when not life-threatening [1, 3]. Although some single tests, such as blood testing and chest X-rays, are performed rapidly, other diagnostic studies, including CT scans, magnetic resonance imaging and digestive endoscopies, which are usually carried out at reference hospitals, may take several weeks even when malignancy is suspected.
Spanish physicians and patients frequently use the ED to circumvent the time-consuming process of PHC referrals to a specialist or for diagnostic tests [4], potentially contributing to ED overcrowding and increased hospital admissions. The delays involved in the diagnostic and referral process have led to a search for alternatives, most notably hospital-based quick diagnosis units (QDU) for patients with suspected serious disease such as anemia or cancer [4, 5]. Besides avoiding hospitalizations and PHC referrals to ED [6], the QDU model has demonstrated equal efficacy, lower costs and greater patient satisfaction compared with conventional admissions [4–6].
The main objective of this study was to determine whether QDU patients referred to ED from PHC could have been safely referred to QDU from the beginning, thus avoiding ED visits. We also determined the appropriateness of direct QDU referrals from PHC and, as a secondary objective of the study, the proportion of QDU patients who might have been evaluated in a less rapid, non-QDU setting.
Characteristics and functioning of the unit
In the setting of an 865-bed tertiary hospital in Barcelona (Spain) attending a population of 540,000, the outpatient internal medicine QDU assesses patients with suspected serious disease processes who are well enough to attend several appointments for diagnostic tests and QDU visits; therefore, they should ideally be stable clinically, mentally and physically capable of attending such outpatient appointments, in order to undergo quick diagnostic examinations [5, 6]. Patients with some pulmonary disorders such as lung nodes are normally evaluated by the respiratory disease day center, although QDU evaluation is not ruled out. Referrals come mainly from the hospital ED and a network of 12 PHC centers after training in the referral criteria, and self-referral is not permitted. Referral by e-mail or fax warrants some control of the appropriateness of the referral.
The unit is run by an internal medicine specialist and a nurse, who are assisted by physicians from other specialties. It has a consulting room and a waiting room for patients and companions, and operates daily. The QDU physician and nurse dedicate 5-hours daily, from Monday to Friday, to QDU work. The QDU work is based on a rapid first visit, followed by preferential arrangement of diagnostic investigations and successive visits until a diagnosis is reached. In particular, in addition to a complete anamnesis and physical examination, all patients have laboratory tests during the first appointment, mainly blood and urine analysis (or stool analysis) and chest X-rays if needed. Blood transfusions are given as required in the daycare center of another hospital department. During the following QDU visits, patients’ outcome is evaluated and results of diagnostic tests are checked over. Further examinations are performed according to the results of previous ones or the clinical course of the disease.
We performed a cross-sectional retrospective study of patients attended by the QDU who fulfilled previously established QDU referral criteria (Table 1) [6]. To avoid potential biases, patients fulfilling referral criteria who did not complete the QDU evaluation due to hospitalization or death, and patients lost to follow-up were also included. The study was approved by the research ethics committee of the Hospital Clínic of Barcelona.
Table 1 Referral criteria of QDU[6]
Patients included were categorized in 2 groups: 1) patients referred from PHC to QDU (PHC-QDU) and 2) patients referred from PHC to ED, and then to QDU (PHC-ED-QDU). All patients were attended between December 2007 and December 2012, with some having been enrolled in a former prospective study [6].
All patients underwent a complete diagnostic workup according to the protocols for each condition. Diagnoses were made by the QDU physician according to the International Statistical Classification of Diseases and Related Health Problems (Tenth Revision) before onward referral [7].
During the period March-May 2013, two observers (senior internal medicine residents with at least 4-years’ training in general internal medicine wards and QDU) independently reviewed all medical records to assess individual appropriateness of each referral. We estimated the proportion of PHC-ED-QDU patients who might have been safely referred to QDU first, avoiding the ED, and the proportion in whom the ED was an appropriate choice. In PHC-QDU patients, we estimated the proportion in whom the QDU was an appropriate choice and the proportion of patients for whom attending the ED first would have been more appropriate.
A scoring system for objectively assessing the appropriateness of referrals to QDU and ED was devised using key criteria. Firstly, the clinical stability/severity of the patient condition at the time of referral to QDU or ED was itemized in a standardized form and scored using a system based on the Acute Physiology and Chronic Health Evaluation II (APACHE II) severity of disease classification system, originally designed to determine the disease severity of adult patients admitted to intensive care units [8]. Briefly, we scored physiological variables including blood pressure, heart rate, temperature, respiratory rate, oxygen saturation or, when available, partial oxygen pressure, arterial pH (when available), Glasgow coma score, serum creatinine, sodium, potassium, hematocrit and white blood cell count. In addition, we entered the presence of chronic organ insufficiency (liver, renal, cardiovascular and respiratory) or an immunocompromised state and a chronic health score was determined. In line with the APACHE II scoring system [8], we added together age points plus total physiology score plus chronic health points to make the total APACHE II score. Secondly, clinically active presence of the following manifestations at the time of referral was also tabulated and scored: dyspnea, decompensated heart failure, pain and pain severity (according to the 0–10 Numeric Rating Scale [9], calculated at the first QDU visit), anemic syndrome, worsening anemia at PHC (i.e., PHC follow-up showing decreasing hemoglobin and hematocrit levels; see below hospital access to PHC electronic health records), vomiting, diarrhea, external bleeding, fever, decreased oral intake, dysphagia, dehydration, edemas and/or anasarca, single or multiple dyselectrolytemia, and malnutrition laboratory findings. Thirdly, the QDU physician assessment of patient comorbidities and health-related quality of life/functional status using the Charlson score (used to assess the burden of chronic illness) [10] and the SF-12 survey administered at the first QDU visit (a multipurpose short form survey with 12 questions that assesses physical functioning, role limitations due to emotional, health problems, and mental health as well as health concepts like bodily pain, general health, vitality, and social functioning [11]) was also introduced in the worksheet. For patients aged ≥ 70 years, we entered the functional capacity for basic activities of daily living (systematically measured in the QDU using the modified, 10-item Barthel index [12]).
In a separate analysis, medical records from all PHC-QDU and PHC-ED-QDU patients were reviewed by the QDU attending physician (a consultant internist with 28 years’ clinical experience in general internal medicine and emergency medicine) in an attempt to estimate the potential proportion of patients who might have been studied in a less rapid, non-QDU setting such as the hospital outpatient clinics or the own PHC centers. For this purpose, data of each patient during his or her PHC evaluation, before QDU or ED referral, were carefully assessed. Besides reviewing the patient information contained in the PHC formal referral sheets, we searched and examined the electronic health records at the different PHC centers, which can be accessed from the hospital system. Since 2007, electronic medical records of patients evaluated at the hospital and its PHC centers can be visualized and shared by their corresponding physicians. We read PHC physicians’ notes at successive patients appointments to understand the reason for their referral decision. For each patient, PHC information was itemized and scored using spreadsheets standardized for each reason for consultation (i.e., febrile syndrome, anemia, unintentional weight loss and so on). Briefly, in addition to any recorded details about patient medical history (e.g., number of comorbidities), general health and functional status, quality of life or degree of dependence that could have influenced referral decisions, we scored relevant symptoms of the current process under investigation, abnormal findings on physical examination (e.g. characteristics of peripheral adenopathies in patients with such a reason for consultation), disease duration, number of PHC and ED visits (and any hospitalization) in the last 6 months, results from preliminary diagnostic tests (e.g. fecal occult blood tests in patients whose reason for consultation was anemia), and treatments that could have induced referral decisions (e.g., treatment with iron or long-lasting use of anticoagulants for cardiovascular diseases in patients with iron-deficiency anemia). For consistency purposes, all the tabulated PHC information was checked against the QDU and ED (in PHC-ED-QDU patients) information.
Normally distributed continuous variables were expressed as mean and standard deviation and assessed using the student’s t test, and skewed variables were expressed as median and 25% and 75% percentiles and assessed using the Mann–Whitney U non-parametric test. Multivariate logistic regression analysis was performed to identify the factors associated with the dependent variable ‘ED referral’ and the odds ratios (OR) with 95% confidence intervals (CI) for the factors were calculated. A P value smaller than .05 was considered statistically significant. Interobserver agreement was assessed by tabulating the distribution of each observer’s results, noting the percentage agreement and calculating the kappa index with their CI. We used the following guidelines to interpret kappa statistic: <0.20, poor agreement; 0.20–0.40; fair agreement; 0.41–0.60, moderate agreement; 0.61–0.80, good agreement; and 0.81–1.00, excellent agreement [13]. All analyses were done using the SAS v.9.1 statistical package (SAS, Cary, North Carolina).
Patients evaluated
A total of 2190 patients were evaluated, including 1186 PHC-QDU patients and 1004 PHC-ED-QDU patients. Of PHC-QDU patients, 4 were hospitalized, 2 died and 3 were lost to follow-up. Of PHC-ED-QDU patients, 3 were hospitalized, 2 died and 2 were lost to follow-up.
Patients’ characteristics
General characteristics are shown in Table 2. The wait for the first QDU visit was significantly longer in PHC-QDU patients, with no differences being observed with respect to age, Charlson comorbidity index, visits per patients, time to diagnosis, and onward referral.
Table 2 Main characteristics and differences of the two groups of patients
Appropriateness of referrals
Based on the review of medical records and the total score per patient, we estimated that initial ED visits might have been avoided by direct referral to QDU in 93.1% of PHC-ED-QDU patients. Nevertheless, 36 (3.6% of PHC-ED-QDU patients) patients with anemia were appropriately referred to ED vs. 3.3% of patients with the remaining conditions.
Among PHC-QDU patients, 96% were considered to be appropriately referred to QDU. However, 8 (0.7%) patients with anemia (4.1% of PHC-QDU patients with anemia) had a follow-up showing a decreasing hemoglobin level during the QDU evaluation, which prompted blood transfusion or treatment with intravenous iron in all them. While 1 of these patients had to be hospitalized, the remaining 7 continued their QDU study without further events. In addition, 1 PHC-QDU patient with pancreatic cancer who had also been appropriately referred died during the QDU evaluation and postmortem examination revealed massive pulmonary embolism. Referrals were considered inappropriate in 4% of PHC-QDU patients, most notably 1.8% (n = 21) of patients with anemia who should have been referred to ED first (Table 3).
Table 3 Number of PHC-QDU patients who should have been referred to the ED and of PHC-ED-QDU patients who should have been directly referred to the QDU according to the reason for consultation
QDU referrals were also considered inappropriate in 4 out of 6 PHC-QDU patients who were eventually hospitalized or died and in 3 out of 5 PHC-ED-QDU patients who were hospitalized or died.
Potential evaluation in a less rapid, non-QDU setting
Although, as explained, all patients fulfilled QDU referral criteria, the QDU physician estimated that 217 (18.3%) PHC-QDU patients might have been studied in another less rapid, less acute setting. (e.g., outpatient clinic or the own PHC center). In addition, a non-QDU evaluation might have been more appropriate in 19 out of 1004 (1.9%) PHC-ED-QDU patients.
Interobserver agreement
The agreement of the appropriateness/inappropriateness of patients directly referred from PHC to QDU (PHC-QDU group) was rated as excellent, while it was rated as good for patients referred from PHC to ED (PHC-ED-QDU group) (Table 4).
Table 4 Interobserver agreement of the appropriateness/inappropriateness of referrals
Reasons for consultation
Table 5 shows the 13 main reasons for consultation and their differences between the 2 groups. Significantly more PHC-ED-QDU patients presented with anemia, febrile syndrome and rectorrhagia than PHC-QDU patients, while significantly more PHC-QDU patients presented with unintentional weight loss than PHC-ED-QDU patients.
Table 5 Main reasons for consultation and differences of the two groups of patients
PHC-QDU patients had a significantly higher prevalence of malignancies compared to PHC-ED-QDU patients. In contrast, PHC-ED-QDU patients had a significantly higher prevalence of non-malignancy-related iron-deficiency anemia, benign colonic disorders and acute viral illness compared to PHC-QDU patients (Table 6).
Table 6 Main diagnoses and differences of the two groups of patients
Patients’ characteristics according to the reason for consultation
Additional file 1: Table S1 shows the main demographic and clinical characteristics and time to diagnosis of the 2 groups of patients according to the 8 main reasons for consultation. Significant differences were observed with regard to anemia: while PHC-QDU patients with anemia were older than PHC-ED-QDU patients, PHC-ED-QDU patients had lower hemoglobin concentrations, presented with more anemic syndrome and required more blood transfusions than PHC-QDU patients.
In the multivariate analysis, anemia (OR 2.87, 95% CI 1.49–4.55, P < .001), rectorrhagia (OR 2.18, 95% CI 1.10–3.77, P = .01) and febrile syndrome (OR 2.53, 95% CI 1.33-4.12, P = .002) were independent factors associated with ED referral.
Our results show that over 90% of patients referred from PHC to ED might have been directly referred to QDU, avoiding interposed ED visits. This causes inconvenience to patient and physician alike.
A large proportion of the increase in ED use in developed countries may be due to wasteful and inefficient inappropriate visits [14] which, one estimate suggests, may result in overuse costing $38 billion a year in the USA [15, 16], with 7-89% of ED visits in different countries reportedly for non-urgent problems susceptible to less specialized care [17]. Factors influencing this situation may include inconsistent definitions of appropriateness and non-urgent triage. Indeed, such a wide range of inappropriate ED attendances underlines the difficulty in ascertaining their true rate.
A recent US study showed that the presenting complaints of patients finally diagnosed with non-urgent disorders or with more severe disorders overlap extensively, suggesting that rather than blaming patients or physicians when the disorder is identified as non-severe, greater integration of care levels should be emphasized [18]. Although most QDU patients have non-specific symptoms, making objective classification of urgent conditions difficult, we estimated that ED referrals were theoretically appropriate in a minority of patients. Although the research question of our study was primary related to referral decision-making and not the cost of care, some cost implications may be inferred. A single visit to our hospital ED, with or without basic tests, including laboratory analysis, simple x-ray and an electrocardiogram, has a raw cost to the patient of €223, compared with €117 for a QDU visit. Thus, although > 90% of study patients had public health insurance and the evaluation was free, a direct QDU referral would have avoided a virtual cost of €208,505. Nevertheless, the number of patients referred to ED form PHC with disorders potentially evaluable at QDU make up a minimal share of the total number of daily ED attendances at our hospital (roughly 0.8%) (data not shown), meaning that any such cost inferences are likely negligible.
Emergency admissions have also increased and now represent around 65% of hospital bed occupancy in England, at a cost of $17 billion [19, 20]. Although yearly emergency admissions have risen by 37% in the last decade, 29% are potentially avoidable [19]. A Norwegian report found that around 20% of emergency admissions were avoidable, with other options, including next-day appointments at specialist outpatient clinics, being available [21]. In the USA, between 2003 and 2009, virtually all of the increase in hospitalizations was due to unplanned admissions from ED (17% increase), suggesting that PHC physicians were referring some of the patients they would previously have hospitalized to ED. Reportedly, US PHC physicians are increasingly relying on ED to diagnose complex patients with potentially serious conditions, rather than handling these patients themselves [22].
The wait for the first QDU visit was longer in PHC-QDU patients, mainly because PHC referrals require pre-appointment checking by the QDU physician [6], while QDU patients referred from ED are seen much more rapidly, without need for previous checking. Although these waiting time differences were statistically significant, they were probably not clinically meaningful. However, even though the mean PHC-QDU delay was only a few days, some were as long as 8 days, and 30% of PHC-QDU patients had a diagnosis of malignant neoplasm, mainly pancreatic cancer. PHC delays in the investigation and onward referral of patients with suspected cancer and of patients not recognizing or acting upon suspicious symptoms are a serious concern and may partly explain the bad outcomes of malignant disease in the United Kingdom and Denmark [23–26].
Referrals to ED were more likely in patients with anemia, rectorrhagia and febrile syndrome. Studies show that anemia and cancer are the most-recorded diagnoses in Spanish QDU patients [4, 5, 27, 28]. Likewise, the main reasons for hospitalization for diagnostic tests in Spain are severe anemia and suspected cancer-related unintentional weight loss [4–6, 27–29]. Anemia, with or without symptoms, with hemoglobin levels below 8–9 g/l, has traditionally been a criterion for admission in our hospital [4, 6]. However, since the introduction of the QDU, patients with anemia referred from PHC to ED are frequently transfused and treated in the ED before safer transfer to QDU. Patients with anemia attended in ED had significantly lower hemoglobin concentrations, more anemic syndrome and greater transfusion requirements than anemic patients referred directly to QDU, suggesting that PHC physicians assessed patients referred to ED as having a more severe disease. The fact that more patients attended in ED presented febrile syndrome and rectorrhagia may be explained by a similar rationale. Although, during the study period, patients with anemia could not be transfused in the own QDU but in a “borrowed” daycare center, this limitation has been solved as of October 2013 when the unit was integrated in an internal medicine-based daycare center.
Our study has some implications. First, the appointment process for QDU patients attended in ED has been changed. Since most of these patients are appropriately referred to QDU, since April 20013, direct electronic QDU appointments are allowed. However, checking is still needed for PHC referrals. Thus, although all study patients fulfilled the QDU referral criteria, we estimated that 18% of PHC-QDU patients might have been studied in a less rapid setting. Although the goal is as many direct referrals from PHC to QDU as possible, avoiding intermediate ED referrals and delays, these referral decisions may lead to unnecessary QDU overcrowding. In order to permit direct referrals (and perhaps even PHC direct electronic appointments) without previous checking, a narrower definition of current QDU referral criteria (Table 1) may be needed. For instance, we may need to clarify that preferably “hard and fixed, > 1 cm adenopathies” and not just “adenopathies” will be evaluated, or “unintentional weight loss, after reasonably excluding a depressive disorder”.
There is an increasing need for alternatives to hospitalization, which has been exacerbated by the reductions in real healthcare spending due to the financial crisis [4, 30]. Although the QDU model provides a valuable and less costly alternative for the diagnosis of a specific, but large, group of patients, the PHC referral process requires some improvement, which may be achieved following a redefinition of the QDU evaluation criteria. Although the QDU may be more suitable for public healthcare systems, the goals of reducing costs, ED overcrowding and inappropriate admissions are shared by both private and public systems [5]. In the USA, the problem of ED overuse is not only a result of PHC lack of access. A recent report found that ED are being increasingly used by PHC physicians to do quick diagnostic studies of patients with potentially serious conditions. The report indicates that ED have direct, immediate access to advanced diagnostic tools such as magnetic resonance imaging, CT scans and nuclear scans, which are seldom accessible elsewhere or would take much longer if ordered from an outpatient setting [22].
The study limitations include the fact that it took place in a single center. However, the unit received patients from 12 PHC centers and the population attended is representative of that of other Spanish QDU, according to published reports [27–29, 31, 32]. In addition, although the appropriateness of PHC referrals to QDU and ED was objectively assessed using a scoring system, the possibility of some perception bias cannot be excluded. It can also be argued that review and scoring of medical records by somewhat junior hospital physicians (i.e., senior residents) is exposed to bias and that a better approach would have been to incorporate a PHC physician on the review group. Likewise, the possibility of some subjective assessment by the QDU attending physician at the time of scoring patients who might have been evaluated in a non-QDU setting cannot be ruled out either. Furthermore, the retrospective design represents a methodological concern because only patients who ended up in the QDU were evaluated, thus limiting the conclusions that can be drawn about the appropriateness of referrals. For instance, although the PHC-ED-QDU group did not include patients referred from PHC to ED who were then hospitalized or discharged after treatment, it is possible that a substantial proportion of such patients were properly referred to ED. Finally, our study did not address the question of why physicians who referred patients to ED decided not to use the QDU instead. Presumably, physicians who referred patients to ED also had the QDU as an option. Since the referring PHC physicians were given a list of conditions for which QDU referral was appropriate, and all patients referred to QDU indeed fulfilled the evaluation criteria, some physicians may have: 1) made the decision to refer to ED and not QDU based on their judgment of the patient condition; 2) had more confidence in ED than QDU; or 3) were unaware or had no clear knowledge of QDU referral criteria. In any way, it is imperative to bear in mind the PHC physicians’ perspectives, as these physicians may find themselves faced with a challenging clinical puzzle that they may not have the skills or time to solve and even delays of some days to have the patient evaluated may be discouraging. Similarly, there may be logical justifications why a PHC physician referred a patient to ED at the time of patient encounter that cannot be determined by a retrospective review of medical records and elements such as social factors, patient choices and circumstances, or even time of day, might all have had some effect. Therefore, we cannot infer from our results that those 93% of patients who might have been directly referred to QDU instead of ED represented “incorrect” decisions; the PHC physician’s decision-making process would actually require additional investigation. A stronger methodology through a prospective study in which, for instance, a PHC physician is promptly contacted anytime he or she refers a patient meeting QDU referral criteria to ED and the reason why he or she has made the decision is discussed, would be helpful to appreciate his or her decision-making process. A future such study evaluating this process, perhaps including also an assessment of physicians’ attitudes and aptitudes, could be valuable.
In summary, over 90% of patients who were referred to ED from 12 PHC centers might have been directly referred to QDU, avoiding the inconvenience of the ED visit. In contrast, most patients referred to QDU first were appropriately referred to it. Anemia, rectorrhagia and febrile syndrome were independent factors associated with ED referral. Although it may seem paradoxical that the mean wait for the first QDU visit was longer in PHC-QDU than in PHC-ED-QDU patients, this is mainly explained by the fact that PHC-QDU referrals require pre-appointment checking by the QDU physician, while patients referred from ED do not. Since we also found that nearly one-fifth of all QDU patients might have been studied in a less rapid, less acute, non-QDU setting, a narrower definition of QDU evaluation criteria may be needed to improve and hasten referrals from PHC.
Xavier Bosch is the QDU attending physician at the Department of Internal Medicine. Ona Escoda, David Nicolás, Emmanuel Coloma and Sara Fernández are residents at the Department of Internal Medicine. Antonio Coca is the director of the Clinical Institute of Medicine and Dermatology (ICMiD). Alfonso López-Soto is the head of the Department of Internal Medicine. All the authors are affiliated with the Hospital Clínic and the University of Barcelona.
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We thank the University of Barcelona for funding the open-access publication of this manuscript.
Department of Internal Medicine, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Villarroel 170, Barcelona, 08036, Spain
, Ona Escoda
, David Nicolás
, Emmanuel Coloma
, Sara Fernández
, Antonio Coca
& Alfonso López-Soto
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Correspondence to Xavier Bosch.
XB drafted the manuscript, coordinated the study, participated in the conception and design of the study, acquisition of data and statistical analysis, OE participated in the acquisition of data and statistical analysis. DN participated in the acquisition of data. EC participated in the acquisition of data and statistical analysis. SF participated in the acquisition of data. AC helped to draft the manuscript. ALS participated in the conception and design of the study and helped to draft the manuscript. All authors participated in the analysis and interpretation of data, revised the manuscript for intellectual content and read and approved the final manuscript.
Additional file 1: Table S1: Main characteristics and differences of the two groups of patients according to the eight main reasons for consultation. Data expressed as mean (SD) and median [25th-75th percentiles] or number (percentage). PHC denotes primary care; QDU, quick diagnosis unit; ED, emergency department; Charlson com in., Charlson comorbidity index; GI, gastrointestinal; NS, nonsignificant; IBS, irritable bowel syndrome; CLD, chronic liver disease. (DOCX 23 KB)
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Bosch, X., Escoda, O., Nicolás, D. et al. Primary care referrals of patients with potentially serious diseases to the emergency department or a quick diagnosis unit: a cross-sectional retrospective study. BMC Fam Pract 15, 75 (2014) doi:10.1186/1471-2296-15-75
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Somatisation: illness perspectives of asylum seeker and refugee patients from the former country of Yugoslavia
Noelle Junod Perron1 &
Patricia Hudelson1
BMC Family Practice volume 7, Article number: 10 (2006) Cite this article
Somatisation is particularly challenging in multicultural contexts where patients and physicians often differ in terms of their illness-related beliefs and practices and health care expectations. This paper reports on a exploratory study aimed at better understanding how asylum seeker and refugee patients from the former country of Yugoslavia who were identified by their physicians as somatising make sense of their suffering.
We conducted semi-structured interviews with 26 asylum seeker and refugee patients from the former country of Yugoslavia who attended the general medicine outpatient clinic of a Swiss teaching Hospital and were identified as presenting with somatisation. Interviews explored patients' illness perspectives and health care expectations. Interviews were audio taped, transcribed verbatim and analyzed to identify key themes in patients' narratives.
Patients attributed the onset of symptoms to past traumatic experiences and tended to attribute their persistence to current living conditions and uncertain legal status. Patients formulated their suffering in both medical and social/legal terms, and sought help from physicians for both types of problems.
Awareness of how asylum seeker and refugee patients make sense of their suffering can help physicians to better understand patients' expectations of the clinical encounter, and the particular nature and constraints of the patient-provider relationship in the context of asylum.
In primary care, 10–35% of patients present physical symptoms that appear to be unrelated to organic pathology [1–3]. These may be variously referred to as "medically unexplained symptoms", functional somatic symptoms or somatisation, reflecting the degree to which such symptoms are understood as an abnormality in the physical functioning of the body that can not be detected in terms of observable structural changes or as problem of psychosocial etiology [4]. Regardless of the term used, however, most researchers and clinicians consider such symptoms to be a reflection of psychological and emotional problems [5, 6].
Somatisation is challenging because physicians and patients often disagree about the causes, meaning, severity and treatment of such symptoms[7, 8]. Somatisation can be particularly challenging in multicultural contexts where social, cultural and linguistic differences between patients and physicians can create additional barriers to communication and to development of a therapeutic alliance with the patient [9, 10].
In Geneva, Switzerland, nearly 40% of the population is foreign born, and physicians frequently encounter difficulties caring for patients from diverse social and cultural background. Two studies conducted at the general medicine outpatient clinic at the Geneva University found that physicians felt particularly challenged by somatising immigrant patients [11, 12]. They described them as unable to verbally express their emotions or to make the link between psycho-social events and physical symptoms, and wondered whether patients' cultural beliefs prevented them from accepting the psychological basis of their symptoms. The physicians were also frustrated by what they felt were patients' inappropriate and unrealistic expectations of physicians and of the health care system. These physicians felt particularly unable to bridge the cultural and communication divide they experienced with asylum and refugee patients from the former country of Yugoslavia who presented with somatisation.
The purpose of the current study was two-fold: to gain insight into the illness related beliefs and health care expectations of asylum and refugee patients from former Yugoslavia who had been identified by their physicians as presenting with somatisation; and to provide information that could be incorporated into junior doctors' training activities aimed at strengthening their ability to care for socially and culturally diverse patients.
In Switzerland, asylum seekers and refugees represent 1.3% of the total population living in the country. Most come from Africa, the Middle East and the Balkans. On average, 22 000 people have applied every year between 2000 and 2002. The asylum process can last up to several years after which only 6.4% of asylum applications are accepted. While awaiting a decision, asylum seekers receive welfare benefits (considered to be relatively high compare to other European countries) and basic medical insurance [13]. They are housed initially in shared rooms or dormitories and then generally move to small, independent apartments. Children attend school and adults may seek employment after 3 months.
The study was conducted at the outpatient clinic of the Community Medicine Department, which is part of the Geneva University Hospitals, Switzerland. The clinic (referred to locally as the Polimed) conducts approximately 12 000 scheduled and 12 000 unscheduled consultations per year with patients over the age of 16 years. In 2002, refugees and asylum seekers made up approximately 30% of scheduled consultations. A pool of trained interpreters is made available free-of-charge to patients. Care is provided by 15–18 junior doctors who spend one year working at the Polimed as part of their training in general or internal medicine.
Study design and data collection
The interviews began with an open-ended question aimed at eliciting the patients' illness narrative ("Please tell me about your illness"). This was then followed by a series of probes aimed at exploring the patients' perceptions of the cause, severity and expected evolution of the illness, the impact of the illness on the patient's life and any illness-related worries, the patients' coping strategies, and the patient's health care expectations. All interviews were conducted by the same person (NJP) in French, with the assistance of professional medical interpreters. Interpreters were instructed to translate word-for-word when possible, and to indicate when they encountered difficulties or confusion. Interviews generally lasted 90–120 minutes. The study was approved by the Geneva University Hospitals Research Ethics Committee.
Fourteen junior doctors working at the Polimed in 2002 were presented with a list of all patients they had seen by appointment during the previous 6 months and were asked to identify which patients they considered to be somatisers. We excluded two other doctors who started to work only a few months before the study started because we felt that their experience with patients was too short. Although we did not provide the doctors with a definition of somatisation, a previous study at the Polimed found that junior doctors generally defined somatisation as the presence of vague, repetitive symptoms in the absence of evidence of objective physiological or biological functioning [11]. They also all considered somatisation to be the physical expression of psychological or social distress or as a sign of underlying psychiatric morbidity [11]. In this study, we were interested in exploring the illness perspectives of patients who were identified by their doctors as somatisers and therefore difficult to care for. Ten percent of their patients were identified as somatisers, with the largest proportion coming from the former country of Yugoslavia (41%, n = 72) and having a refugee or asylum seeker status. Since junior physicians considered these patients to be particularly challenging, we decided to focus our study on this population. A review of the medical files revealed that most of the patients from former Yugoslavia described as somatisers had also diagnoses of depression, anxiety and/or post-traumatic stress disorders. Only a small minority were exclusively diagnosed with somatoform disorders.
From the total list of 72 patients, we interviewed a convenience sample of 26 patients. Patients considered by their physicians to be too fragile to undergo interviews where past trauma might be evoked were excluded (10), as were patients with invalid addresses and telephone numbers (7). We invited a total of 31 patients to participate in the study; 5 patients declined because they associated our interviews with asylum hearings. Written, informed consent was obtained through professional interpreters in patients' native language.
We compared sociodemographic characteristics of participants and non-participants and found that while participants were slightly younger (mean 36 vs 41 years) and more came from Kosovo (54% vs 28%), there were no significant differences between participants and non-participants in terms of sex, religion, place of residence, legal status, length of time in Switzerland, length of follow-up at the outpatient clinic and psychiatric co-morbidity.
Qualitative analysis
Interviews were tape-recorded, and translators' utterances were transcribed verbatim. No back translation was conducted.
Analysis of transcripts followed an "editing style" approach [14], and focused primarily on identifying patients' perceptions of the cause, severity and expected evolution of the illness, the impact of the illness on the patient's life and any illness-related worries, the patients' coping strategies, and the patient's health care expectations. Both authors read each transcript, identifying key passages which corresponded to the topics of interest. The authors then discussed each transcript, comparing and contrasting their observations and developing codes. Once consensus was reached on an overall coding scheme, NJP coded all interviews using Winmax software for qualitative analysis [15]. Coded segments were then reviewed by PH, and any differences in opinion about coding were then discussed and resolved. Data display tables were then created to facilitate the examination of similarities and differences across respondents to identify key themes.
Twenty six patients participated in the study. Most of them were female asylum seekers from Bosnia and Kosovo, living with family members in rented flats (See Table 1 for patient characteristics). The main complaints were headaches (20/26), fatigue (12/26), bone and joint pains 17/26), nervousness (18/26), sleep disturbances (7/26) and anxiety (12/26).
Table 1 Socio-demographic characteristics of study participants
The role of pre-migration experiences in explaining illness
Most patients (19/26) made a link between present symptoms and past traumatic experiences. Traumatic events such as war, flight and loss of loved ones were often mentioned to explain how and why their symptoms started.
≪ It was the war, when we were fleeing...we suffered a lot. Because I didn't have pain like this before...And then there were members of my family that were killed as well. There's an underlying nervousness that....yes, I have stomach pains and my body trembles and I'm exhausted..." (P9)
≪ It's the war. We are no longer in good health and in the head we're no longer normal. This is all since the war. ≫ (P13)
However, even patients who did not attribute their health problems traumatic events reported that their symptoms worsened when they thought about the past.
"But the epilepsy comes more often when I think..[When you think, what kind of thoughts do you have?] ...about the past..."(P2)
"When I first arrived, I had headaches all the time. Now I have them less often. [When do you get them?] It hurts the worst when I think about something bad, when I think about the past...I tell myself all sorts of things in my head and then I start to hurt." (P7)
While most patients believed that past traumatic experiences were the cause of their present symptoms, they did not feel that focusing on those experiences would alleviate their suffering. They tended to believe that "what's done is done" and that one had to learn to live with it.
≪ You don't suffer like that for no reason. I'm disturbed by what happened. I'm disturbed because I think about my husband. He was the man of my life. Life goes on, one has to live, but even so the memories come back...I can't do anything...what happened has happened ≫. (P6)
Even though patients made an association between past traumatic experiences and current symptoms, this did not preclude belief in a physical cause of their suffering as well. Many patients were convinced that their pre-migration experiences had caused some sort of physical damage, and that this physical damage was the true underlying cause of their symptoms.
"I was destroyed as a result of the past, and then the illness made me worse". (P1)
Patients sought to identify and treat the underlying physical cause of their symptoms, and for five informants the absence of organic findings fueled their fears about serious illness, functional disability and even death.
≪ If I didn't have something, I wouldn't hurt. But they tell me "you're fine." I don't know what to say ... ≫ (P9)
≪ I don't know what I have. They did tests, they don't know what I have...What worries me the most is that I'm young, and I'm afraid, and I'm always thinking that I'm going to die..." (P2)
The role of post-migration experiences in explaining persistence of symptoms
While patients talked about pre-migration experiences as the underlying cause of their illness, they talked about current life conditions as perpetuating their symptoms and posing barriers to improvement. They felt that financial worries (4/26), worries about their children (7/26), uncertainty about the future (14/26), fear of expulsion (14/26), and lack of social support (7/26) made them vulnerable to chronic and worsening physical and psychological symptoms.
"When I start to think again, I think about all the problems around me. My past, my children, what happened to me, what could happen to me...What's going to happen with my life, the life of my children, what they're going to do in life...And then it starts again, I feel bad, I have pain. ≫ (P17)
≪ Fear is always present. Especially when you're at home, when you don't have any work, when you have lots of worries...such as how to feed and school the children. It's so many things...and it's clear that then you hurt all over" (P23)
Medical care as an answer to both physical and social problems
Patients believed their symptoms were caused by "real" or organic problems, even if not yet identified, and that post-migration social conditions contributed to their chronicity. As a result, patients sought both medical and social solutions to their suffering. Patients put much emphasis on being examined, doing tests (14/26) and receiving medical treatment (23/26) but also felt that their well-being depended on resolving their practical social problems.
≪ What should be done to improve your health?" "First, get legal status here. Or at least receive a clear response: 'You can stay' or 'You cannot stay'... at least that way I can know." (P24)
≪ How did you feel when you got your B permit (legal status)? " "I felt relieved...which is totally normal...I told myself I'm going to stay here for awhile because my children are going to finish school here, and they won't be pulled apart in terms of schooling...that made me feel a lot better" (P17)
Interestingly, some patients looked to physicians to help them resolve their social problems (6/26). While they did not consider this to be a typical or normal part of a physician's role, they recognized that physicians could potentially provide medical certificates that could help in their request for asylum.
"I don't want to be expelled, I don't want to suffer anymore...I have two friends, they got the B permit (legal status) and say that they got it through their physician." (P9)
Many patients described their isolation and lack of social networks (14/26), and appreciated the openness, respect and understanding shown to them by physicians. While social talk, counseling and expression of emotions was not generally viewed or valued as medical treatment, it was positively experienced as legitimizing their suffering.
"They were interested in me and really took care of me. They told me "whatever you need, we can help you, we can help you...whatever documents you need, we can help you because we know that your life is difficult." (P1)
"She [the doctor] gives me the strength to go on. She tells me "you're going to get better, your wishes will be fulfilled little by little". She says "Little by little you will get better. You need to take classes to learn French. In that way you won't spend all your time thinking about what's happening at home. Sometimes it helps to go out, breathe fresh air..." (P26)
≪ I hoped to be listened to, and really that's what I found because I talk about my worries and [the doctor] listens to me and gives me advice. Basically, he's the only person I can confide in and talk to." (P21)
Only a few patients (5/26) did not enjoy talking, especially when discussions focused on the past.
"I don't like the appointments (with the doctor). I have to describe everything that happened, and how it happened. Afterwards, I feel sick for two weeks" (P3)
In contrast with their experiences at the outpatient clinic, patients' pre-migration health care experiences were characterized by high cost, brief consultations focused on blood tests and medications, poor patient/provider communication and a fear of being labeled as mentally ill.
"I feel good here, because they listen to me, and I can tell everything I have to tell. Back home when we went to the doctor, the doctor didn't even look at you – he just wrote a prescription and that was it. People didn't even greet each other the way they do here when you enter the doctor's office. They didn't even say good morning or good evening or goodbye...the doctor would just ask where you hurt, he would write a prescription and that's it. You didn't talk...whereas here you always have an hour to talk. And back home you always had to bring some sort of bribe for the doctor..." (P10)
≪ What did you do to try to get better (back in Kosovo)?" "I didn't do anything because if I had gone to what we call a neuropsychiatrist I would have been immediately labeled as crazy. Here, it's good, there's a totally different approach." (P5)
Only a minority of patients (3/26) felt that because of their legal status, they did not have the same access to care and did not deserve the same attention as other people.
"When I come to the hospital, I want to have more tests done or at least be hospitalized to do everything, to find out what I have. I asked my doctor. But maybe because I'm a refugee they don't do that". (P2)
Our results indicate that study participants perceived a causal link between their present illness and their pre-migration traumatic experiences. They attributed persistence of their symptoms in part to the difficulties of their current living conditions and their uncertain legal status. However, the fact that patients established a link between their psychological and physical suffering did not preclude their desire to seek medical diagnosis and treatment for their symptoms. Patients believed that their migration-related experiences could cause physical disease or dysfunction, requiring timely investigation and appropriate treatment. Nonetheless they appreciated that physicians helped them with both physical and social/legal problems.
Our finding that somatising patients tended to attribute their suffering to both physical and social causes and to perceive answers and healing strategies outside themselves are consistent with previous studies [16–18]. Other studies have also found that such patterns of response may be reinforced in an immigration context [19–21]. Several studies in different countries show that some immigrants are more prone to develop somatisation than other groups of people and seek more help from primary care physicians than from mental health professionals [22, 23].
The importance of post-migration stressors is supported by studies conducted among refugees communities that demonstrated that distress among refugees persists because of psychosocial maladjustment, lack of social support and acculturation difficulties [24–26]. Separation from family, loneliness, fears of being sent home, poverty and discrimination are considered to negatively influence the mental health of asylum seekers [27, 28].
Our findings suggest also that both previous health care experiences in their home countries and present health care conditions encourage patients to focus on physical symptoms and expect medical and technical solutions to their problems. On the one hand, patients in our study reported that health services in their home country did not generally address psychological distress and that they feared being labelled as mentally ill. Anthropological studies suggest that such situations may incite patients to emphasize physical symptoms of distress [10, 18]. On the other hand, immigrants' free and easy access to high-tech care and a traditionally biomedical approach to health problems in Switzerland may also create high expectations towards medical care and further encourage the physical expression of suffering. This is supported by previous research which shows that the expression of distress through either somatic or psychological symptoms is shaped by the availability, accessibility and structure of the primary care system [18, 29].
At the same time, most patients in our study complained of social isolation and appreciated the psychological and social support they received from their physicians. The fact that they experienced such support almost exclusively in the medical setting may further contribute to the medicalisation of their suffering and encourage them to consider illness as a means to "articulate their social suffering, express their unsatisfactory integration and legitimate their demands for improved living conditions in the host country" [30]. In our country as in many other countries of Europe, only a limited number of asylum seekers are admitted as refugees after many years of procedures. Swiss asylum authorities sometimes rely on medical certificates to make decisions about asylum applications. Because asylum seekers whose medical conditions cannot be adequately treated in their home country can obtain a prolongation of their stay in Switzerland, it may be that the asylum process incites people to frame distress as a medical condition [31]. The asylum context shares many similarities with other contexts of care where social, political and medical issues are closely interlinked (use of post-traumatic stress disorder diagnosis for US veterans and compensation system [31, 32]; low back pain or somatoform disorder and claims for invalidity pensions [33]. In such contexts, the doctor is generally seen not only as a source of health care but also as a gatekeeper or facilitator to social acceptance, financial or legal benefits.
The medical setting and physician status of the interviewer may have influenced the content and emphases of patients' narratives as well [34, 35]. If participants in our study perceived the study interview as another means to legitimizing their suffering and asylum request, their illness narratives may have emphasized what they believe to be of most interest or importance to asylum authorities.
Our study has several weaknesses. We interviewed a convenience sample of patients who may not be representative of all Kosovar and Bosnian patients considered to be somatisers, and the small sample size did not allow us to explore potential differences between asylum seekers and refugees. We also did not check the accuracy of interpreters' translations, although we did use professionally trained medical interpreters who were highly skilled at word-for-word translations. Another potential weakness of our study is that we relied on physicians' diagnoses of somatisation rather using more objective diagnostic criteria. However, our objective was not to verify patients' psychiatric diagnoses, but rather to identify patients whose physicians considered them to have medically unexplained symptoms, and to explore those patients' understanding of their symptoms.
We were also unable to explore how physicians' explanatory models influenced patients' narratives. As Groleau and Kirmayer point out [34], psychophysiological and sociophysiological models provide plausible medical explanations for most common somatic symptoms, and these models can provide a potential bridge to patients' culturally based explanations for their symptoms that link social context with bodily distress. When physicians validate the physical nature and social meaning of patients' suffering, patients are more likely to acknowledge the influence of psychosocial stress on their physical condition. On the other hand, when physicians narrowly psychologise their patients' distress, they tend to shift the responsibility for the unexplained to the patient [36]. Patients may respond by insisting on medical and social answers to their suffering that provide healing strategies outside themselves. Understanding how patients and physicians influence each others' explanatory models and illness narratives is important, but would require a more interactional analysis of patients' symptom attributions and clinical experiences, which is beyond the scope of the current study.
The findings from this exploratory study suggest that these patients' illness perspectives are influenced by both pre- and post-migration life and embedded in a larger socio-political and legal context of asylum. Awareness of how physical, psychological, social and legal aspects intermingle may help physicians to be more open and receptive to the explanations given by patients as to the causes of their distress. In the context of asylum, physicians may need to address both patients' health and social issues in order to develop a trusting, therapeutic alliance [37].
Escobar JI, Gara M, Silver RC, Waitzkin H, Holman A, Compton W: Somatisation disorder in primary care. Br J Psychiatry. 1998, 173: 262-6.
Kroenke K, Price RK: Symptoms in the community. Prevalence, classification, and psychiatric comorbidity. Arch Intern Med. 1993, 153: 2474-80. 10.1001/archinte.153.21.2474.
Goldberg DP, Bridges K: Somatic presentations of psychiatric illness in primary care setting. J Psychosom Res. 1988, 32: 137-44. 10.1016/0022-3999(88)90048-7.
Mayou R, Bass C, Sharpe M: Treatment of functional somatic symptoms. 1995, Oxford: Oxford University Press
Lipowski ZJ: Somatization: the concept and its clinical application. Am J Psychiatry. 1988, 145: 1358-68.
Rosen G, Kleinman A, Katon W: Somatization in family practice: a biopsychosocial approach. J Fam Pract. 1982, 14: 493-502.
Hartz AJ, Noyes R, Bentler SE, Damiano PC, Willard JC, Momany ET: Unexplained symptoms in primary care: perspectives of doctors and patients. Gen Hosp Psychiatry. 2000, 22: 144-52. 10.1016/S0163-8343(00)00060-8.
Glenton C: Chronic back pain sufferers – striving for the sick role. Soc Sci Med. 2003, 57: 2243-52. 10.1016/S0277-9536(03)00130-8.
Cheung P: Somatisation as a presentation in depression and post-traumatic stress disorder among Cambodian refugees. Aust N Z J Psychiatry. 1993, 27: 422-8.
Hsu SI: Somatisation among Asian refugees and immigrants as a culturally-shaped illness behaviour. Ann Acad Med Singapore. 1999, 28: 841-5.
Junod Perron N, Hudelson P: How do junior doctors working in a multicultural context make sense of somatisation?. Swiss Med Wkly. 2005, 135: 475-479.
Hudelson P: Contextualizing cultural competence training of residents: results of a formative research study in Geneva, Switzerland. Accepted for publication in Medical Teacher.
[http://www.asyl.admin.ch]
Miller WL, Crabtree BF: Doing qualitative research: the dance of interpretation. 1999, Thousand Oaks, CA: Sage publication
Kuckartz U: Winmax software for qualitative data analysis. 1998, Thousand Oaks, CA: Scolari Sage Publications, Inc
Peters S, Stanley I, Rose M, Salmon P: Patients with medically unexplained symptoms: sources of patients' authority and implications for demands on medical care. Soc Sci Med. 1998, 46: 559-65. 10.1016/S0277-9536(97)00200-1.
Johansson EE, Hamberg K, Westman G, Lindgren G: The meanings of pain: an exploration of women's descriptions of symptoms. Soc Sci Med. 1999, 48: 1791-802. 10.1016/S0277-9536(99)00080-5.
Kirmayer LJ, Young A: Culture and somatization: clinical, epidemiological, and ethnographic perspectives. Psychosom Med. 1998, 60: 420-30.
Baarnhielm S, Ekblad S: Turkish migrant women encountering health care in Stockholm: a qualitative study of somatization and illness meaning. Cult Med Psychiatry. 2000, 24: 431-52. 10.1023/A:1005671732703.
Markovic M, Manderson L, Kehaler M: The health of immigrant women: Queensland women from former Yugoslavia. J Immigrant Health. 2002, 4: 5-15. 10.1023/A:1013003126561.
Kilcher A, Spiess R: Die hausärtzliche Betreuung von Migranten/-innen mit chronischem Schmerzsyndrom. Schweizerische Ärtzezeitung. 2003, 84: 452-460.
Ritsner M, Ponizovsky A, Kurs R, Modai I: Somatization in an immigrant population in Israel: a community survey of prevalence, risk factors, and help-seeking behavior. Am J Psychiatry. 2000, 157: 385-92. 10.1176/appi.ajp.157.3.385.
Lin EH, Carter WB, Kleinman AM: An exploration of somatization among Asian refugees and immigrants in primary care. Am J Public Health. 1985, 75: 1080-4.
Westermeyer J, Bouafuely M, Neider J, Callies A: Somatization among refugees: an epidemiologic study. Psychosomatics. 1989, 30: 34-43.
Castillo R, Waitzkin H, Ramirez Y, Escobar JI: Somatization in primary care, with a focus on immigrants and refugees. Arch Fam Med. 1995, 4: 637-46. 10.1001/archfami.4.7.637.
Henley A, Schott J: Culture, religion and patient care in a multi-ethnic society: a handbook for professionals'. 1999, London: Age concern
Sinnerbrink I, Silove D, Field A, Steel Z, Manicavasagar V: Compounding of premigration trauma and postmigration stress in asylum seekers. J Psychol. 1997, 131: 463-70.
Silove D, Steel Z, McGorry P, Mohan P: Trauma exposure, postmigration stressors, and symptoms of anxiety, depression and post-traumatic stress in Tamil asylum-seekers: comparison with refugees and immigrants. Acta Psychiatr Scand. 1998, 97: 175-81.
Simon GE, Von Korff M: Somatization and psychiatric disorder in the NIMH Epidemiologic Catchment Area study. Am J Psychiatry. 1991, 148: 1494-500.
Salis Gross C: Struggling with imaginaries of trauma and trust. The refugee experience in Switzerland. Cult Med Psychiatry. 2004, 28: 151-167. 10.1023/B:MEDI.0000034408.60968.eb.
Summerfield D: The invention of post-traumatic stress disorder and the social usefulness of a psychiatric category. Bmj. 2001, 322: 95-98. 10.1136/bmj.322.7278.95.
Young A: The harmony of illusion: inventing posttraumatic distress. 1995, Princeton NJ: Princeton University Press
Hadler NM: If you have to prove you are ill, you can't get well. The object lesson of fibromyalgia. Spine. 1996, 21: 2397-400. 10.1097/00007632-199610150-00021.
Groleau D, Kirmayer LJ: Sociosomatic theory in vietnamese immigrants' narratives of distress. Anthropology & Medicine. 2004, 11: 117-133. 10.1080/13648470410001678631.
Kirmayer LJ: Broken narratives: clinical encounters and the poetics of illness experience. Narrative and the cultural construction of illness and healing. Edited by: Mattingly C, Garro L. 2000, Berkeley: University of California Press
Kirmayer LJ: Mind and body as metaphors: hidden values in biomedicine. Biomedicine examined. Edited by: Lock M, Gordon D. 1988, Dordrecht: Kluwer Academic publishers
Watters C: Emerging paradigms in the mental health care of refugees. Soc Sci Med. 2001, 52: 1709-18. 10.1016/S0277-9536(00)00284-7.
The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/7/10/prepub
We thank Patrick Bovier for his useful comments on an earlier version of the article.
Medical Outpatient Clinic, Department of Community Medicine, Geneva University, Hospitals, Switzerland
Noelle Junod Perron
& Patricia Hudelson
Search for Noelle Junod Perron in:
Search for Patricia Hudelson in:
Correspondence to Noelle Junod Perron.
NJP and PH conceived and designed the study. NJP conducted the interviews. NJP and PH analyzed and interpreted the data and wrote the manuscript.
Junod Perron, N., Hudelson, P. Somatisation: illness perspectives of asylum seeker and refugee patients from the former country of Yugoslavia. BMC Fam Pract 7, 10 (2006) doi:10.1186/1471-2296-7-10
DOI: https://doi.org/10.1186/1471-2296-7-10
Asylum Seeker
Junior Doctor
Illness Narrative
Functional Somatic Symptom
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Электронная книга: Tony Crook «Planning Gain. Providing Infrastructure and Affordable Housing»
Winner of the Royal Town Planning Institute award for research excellence This critical examination of the development and implementation of planning gain is timely given recent changes to the economic and policy environment. The book looks both at the British context as well as experience in other developed economies and takes stock of how the policy has evolved. It examines the rationale for planning gain, how it has delivered substantial funds for infrastructure and affordable housing and, in the light of this, how it might continue to play a role in the funding of these. It also draws on overseas experience, for example on impact fees and public sector land assembly. It looks at lessons from the past for future policy, both for Britain and for countries overseas. Mechanisms to tap development value are also a global phenomenon in developed market economies– whether through formal taxation or negotiated contributions. As fiscal austerity becomes an increasingly challenging issue, ‘planning gain’ has grown in importance as a potential source of funding for infrastructure and new affordable housing, with many countries keen to examine, learn from,and adapt the experience of others. a critical commentary of planning gain as a policy timely post credit crunch analysis addresses recent planning policy changes
Издательство: "John Wiley&Sons Limited"
Купить за 9494.56 руб и скачать на Litres
Former F1 driver
image-size = 150
pixels = 150
Name = Tony Crook
Nationality = flagicon|UK British
Years = F1|1952 - F1|1953
Team(s) = Frazer Nash, Cooper
Races = 2
Championships = 0
Wins = 0
Podiums = 0
Points = 0
Poles = 0
Fastest laps = 0
First race = 1952 British Grand Prix
First win =
Last win =
Last race = 1953 British Grand Prix
Anthony Crook (born in Manchester, February 16, 1920) is a former racing driver from England. He participated in 2 World Championship Formula One Grands Prix, debuting on July 19, 1952. He scored no championship points. He also participated in several non-Championship Formula One races. In 1960 he took over the British car maker Bristol, which he owned until 2001.
Complete World Championship results
Источник: Tony Crook
Tony Crook Planning Gain. Providing Infrastructure and Affordable Housing Winner of the Royal Town Planning Institute award for research excellence This critical examination of the development and implementation of planning gain is timely given recent changes to the… — @John Wiley&Sons Limited, @ @ @
@ Подробнее...
9494.56 электронная книга
Business and Industry Review — ▪ 1999 Introduction Overview Annual Average Rates of Growth of Manufacturing Output, 1980 97, Table Pattern of Output, 1994 97, Table Index Numbers of Production, Employment, and Productivity in Manufacturing Industries, Table (For Annual… … Universalium
Architecture and Civil Engineering — ▪ 2009 Introduction Architecture For Notable Civil Engineering Projects in work or completed in 2008, see Table (Notable Civil Engineering Projects (in work or completed, 2008)). Beijing was the centre of the world of architecture… … Universalium
Computers and Information Systems — ▪ 2009 Introduction Smartphone: The New Computer. The market for the smartphone in reality a handheld computer for Web browsing, e mail, music, and video that was integrated with a cellular telephone continued to grow in 2008. According to… … Universalium
urban planning — n. the study or profession dealing with the growth and functioning of cities and towns, including environmental concerns, zoning, the infrastructure, etc. urban planner n. * * * Programs pursued as a means of improving the urban environment and… … Universalium
Russia — /rush euh/, n. 1. Also called Russian Empire. Russian, Rossiya. a former empire in E Europe and N and W Asia: overthrown by the Russian Revolution 1917. Cap.: St. Petersburg (1703 1917). 2. See Union of Soviet Socialist Republics. 3. See Russian… … Universalium
John Degnan — Infobox Politician name = John A. Degnan imagesize = 225px residence = flagicon|New York|size=30px Brewster, New York office = Mayor of Brewster, New York party = Republican [ Risnit, Michael. [http://www.poughkeepsiejournal.com/apps/pbcs.dll/arti… … Wikipedia
Germany — /jerr meuh nee/, n. a republic in central Europe: after World War II divided into four zones, British, French, U.S., and Soviet, and in 1949 into East Germany and West Germany; East and West Germany were reunited in 1990. 84,068,216; 137,852 sq.… … Universalium
Economic Affairs — ▪ 2006 Introduction In 2005 rising U.S. deficits, tight monetary policies, and higher oil prices triggered by hurricane damage in the Gulf of Mexico were moderating influences on the world economy and on U.S. stock markets, but some other… … Universalium
United States — a republic in the N Western Hemisphere comprising 48 conterminous states, the District of Columbia, and Alaska in North America, and Hawaii in the N Pacific. 267,954,767; conterminous United States, 3,022,387 sq. mi. (7,827,982 sq. km); with… … Universalium
china — /chuy neuh/, n. 1. a translucent ceramic material, biscuit fired at a high temperature, its glaze fired at a low temperature. 2. any porcelain ware. 3. plates, cups, saucers, etc., collectively. 4. figurines made of porcelain or ceramic material … Universalium
China — /chuy neuh/, n. 1. People s Republic of, a country in E Asia. 1,221,591,778; 3,691,502 sq. mi. (9,560,990 sq. km). Cap.: Beijing. 2. Republic of. Also called Nationalist China. a republic consisting mainly of the island of Taiwan off the SE coast … Universalium
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Time Untime
Prepare to enter a world full of richly imagined mythology - a world where dark and dangerous heroes fight to protect us.
Prepare to enter an endless battle. Prepare to lose yourself . . .
The Mayans aren't the only ones with a 2012 prophecy . . .
Long before recorded history, there was a Keetoowah warrior so feared that everyone trembled before his wrath. Only a brutal betrayal by the one closest to him could defeat him. But not even death was the end of a man so strong. The Time Untime approaches . . .
Kateri Avani has been plagued her entire life with dreams she doesn't understand: images of places she's never been and of a man she's never seen. Her quest for answers has driven her to Las Vegas where she hopes to finally silence the demons in her mind. What she never anticipates is coming face to face with the warrior who has haunted her her entire life. One who belongs to a world the scientist in her refuses to believe is real.
Ren Waya came back from the dead to keep the prophecy he began from coming true and ending the world. For thousands of years, he has fought the same evil that once possessed him. But now that evil has found the one person he can't fight. The one person who, against his will, holds the most sacred part of him: his heart. But if he doesn't kill Kateri, the deadliest of evils will reemerge and destroy everyone else on the planet. It was a sacrifice he made once. Will he be able to make it again?
Melli Mel , 09/08/2012
Sherrilyn Kenyon has done it again!!!
A very good read!!! Couldn't put the book down!!
More Books by Sherrilyn Kenyon
Night Pleasures
Fantasy Lover
Night Play
Night Embrace
Son of No One
Dragonbane
Dragonmark
Stygian
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Charity :
Ch. Div. V. C. H.—Charity C‘om1m'su'oners—- Consent to Sula--16 §‘ 17
Vict., c. 137, s. 62; 18 §‘ 19 Vict., c. 124, s. 29.—The Royal Society of
London being licensed to purchase lands and hold them in mortmain,
bought certain lands out of moneys arising from voluntary contributions:
Held that the consent of the Charity Commissioners to the sale of the
lands by the Society was not reqnired.—Re Royal Society and Thompson, 44 L.T. 274.
C. A.—E.rpulsion of M'ember.—Where a club has expelled a member, the Court will enquire whether the expulsion was conducted in accordance with the rules, but will not review the discretion of the club in exercising the power of expulsion unless malice can be shown to have influenced that discreti0n.—-Dawkins v. Antrobus, 29 W.R. 511.
Company :(xxxv.) Ch. Div.V. C. M.—Applicationfor Shares—Allolment—Repudiation——
Ccsts.—A. applied for shares in a company of which G. was director and chairman, by reason of his confidence in G. Before allotment G. resigned his position, and the company allotted shares to A., and told him of the retirement of G. Therenpon A. asked to cancel his application, but the company refused to consent : Held that A.'s name must be removed from the register, with costs of the application as between solicitor and client against the company.—Amlerson’s Case, Re Scottish Petroleum Co., 50 L.J. Ch. 269; 4-3 L.T. 723; 29 W.R. 372.
) C. A.—Agreement by Promoters—Ratification.—A company cannot ratify an agreement mad 3 on its behalf before the company was incorporated.—Re Empress Engineering Co., L.R. 16 Ch. D. 125; 43 L.T. 74-2; 29 W.R. 34.2.
Ch. Div. V. C. H.——-Articles—Bon-owing Powsrs—Capital not called up.——The articles of a company provided that the directors might borrow upon the security of that portion of the capital not called up or of other property of the company a sum not exceeding two-thirds of the capital for the time being not called up. Capital was, by the interpretation clause, to mean the nominal capital from time to time or (as the context might require) the capital moneys from time to time of the company: Held that the capital not called up referred to in the articles included unissued capital.--English Channel Sleamship CO. v. Roll, 44 L.T. 135.
) Ch. Div. F. J'.—Construcii0n of Special Act—-Borrowing Powers-
8 Vict., c. 16, ss. 41, 4-2.—'l'he construction of the special Act of a
company, incorporated for the purpose of draining and reclaiming land,
considered with regard to its power to contract with limited owners,
and to obtain charges on the property drained or reclaimed, and also to
borrow money. Secs. 4-1, 42, of Companies Clauses Act, 1845, do not
make void an instrument the consideration for which is apparent, though
not in terms stated.—Land0wners Drainage and Inclosure Co. v. Ashford, L.R. 16 Ch. D. 4.11; 50 L.J. Ch. 276; 44 L.T. 20. .
Ch. Div. M, R,—Dividends out of Capital—Preference ShareholdersNet I’roflts.—'1'he articles of a limited tramway company provided that dividends should be paid only out of profits, after a reserve fund for maintenance and repairs had been set aside. The directors had, for some time past, failed to set apart a sufiicient reserve fund, and the amount required to restore the plant of the company exceeded the whole of the net profits in the hands of the directors: Held that the company could only declare a dividend out of net profits after making due provision for the maintenance of the tramway ; but the preference shareholders, whose dividends were dependent on the profits of each year, were entitled to a dividend out of the profits of any year after setting aside a proportionate part sufficient for the maintenance of the tramway for that year only.
1869, ss. 31, 49. On the trial of issues it was found that defendant was a promoter of a company and accountable to it for a sum of £108,000 received by him as profit under undisclosed agreements. After the finding of the issues defendant went into liquidation : Held that defendant's liability was incurred by means of fraud and breach of trust within the meaning of sec. 49 of the Bankruptcy Act; and that it was not a demand in the nature of uuliquidated damages arising otherwise
than by reason of a contract, within sec. 31.—Emma Mining Co. v. Grant, 29 W.R. 481.
Injunction-—Companies Act, 1862, s. 20.—I)n motion on behalf of a company. incorporated in 1836, and not registered under the Companies Act, 1862, for an injunction to restrain defendants from registering a new company under a similar name: Held that see. 20 of the Companies Act, 1862, did not apply, and plaintifis not having alleged fraudulent intention on the defendants part, the action was dismissed and leave to amend refused.—Hendricks V. Montagu-, 50 L.J. Ch. 257; 44 L.T. 89.
County C0urt—25 Q’ 26 Vict., c. 89, s. 87; 30 §‘ 31 Vict., c. 131, s. 43; 37 <3" 38 Vict., c. 42, s. 32. —The directors of an incorporated building society gave a depositor a bond in which the funds and assets of the society were declared to be held liable for the repayment of the deposit. The depositor brought an action for foreclosure on the bond, and while the action was pending a winding-up order was made in a County Court, and the Judge refused leave to the depositnr to continue his action: Held that the Companies Acts, 1862 and 1867, apply to the Building Societies Act, 1874, and that an appeal on a matter of discretion lay to the Court ; that the effect of sec. 32 of the last-mentioned Act is to substitute the County Court for the Court of Chancery, and that the bond was not a mortgage. and a foreclosure action could not be maintained upon it.— And/rew v. Swansea Cambrian Building Society, 4-1 L.T. 106; Jones v. Swansea Cambrian Building Society, 29 W.R. 382.
C. P. DiV.—Winding-up—C'ontributary—Sel-nfi'—("o1mter-claim.—A person who has been duly settled on the list of contributories of a company, and on whom calls have been made, cannot,in an action for calls by the liquidator, counter-claim for a debt or damages due to him from the
Act, 1875, s. 10.—'1‘he holder of a policy of insurance against fire granted by a limited company, and which is current at the date of the windingnp of the company, is entitled to prove for the full amount of his policy when a loss by fire exceeding such amount occurs after winding-up and
before the time limited for sending in claims against the company.—Re Northern Counties Fire Insurance Co., 50 L.J. Ch. 278 ; 44 L.T. 299.
Ch, Div, F, J'.—ll'inding- p—Lease ofMine—Retenti0n by Liquidat0r— Rent.—-A coal mine was let to a company by a lease containing a power for the lessor, if rent should remain unpaid for 30 days, to stop the working of the mine and distrain, and if the distress should be insultioient, to enter and determine the lease. Rent became due on November 8rd, and on the 5th the company was ordered to be wound.up. On December 6th the lessor required the liquidator to pay the rent, and stated that otherwise he should apply to the Court to restrain the working. The liquidator did not pay the rent, and continued to work the mine: Held that leave should be given to the lessor to distmin for the full rent which accrued due on November 3rd.—E.r parte Perkins, Re Silkstone &' Dodworth. Coal §r‘ Iron Co., 29 W.R. 484.
l C. .A.-—Winding-up—Lacwe to Sue in Name of Comps/ny.—A company being in course of liquidation, certain costs were ordered to be taxed and paid to R. out of the assets. After taxation the liquidators represented that there were no assets available, and they refused to bring an action against former directors to make them account for moneys alleged to have been improperly received by them. Held that R.’s solicitors were not creditors of the company in respect of the costs ordered to be paid to R., and could not have leave to bring the action in the name of the c0mpany.—Cape Breton Co. v. Fenn, 29 W.R. 386.
Ch. Div. V. C. B.— Wi:u1i11g-up—Secured CrecZilor—-Failure of Security —Judica!m-e Act, 1875, s. l0.—A creditor of a company believing himself to be fully secured by the hypothecation of a call on the company's shares, made no claim in the wiuding.up. It afterwards turned out that his security was defective, owing to the call moneys hypothecated having been paid away : Held that he was entitled to value his security and prove for the balance, not disturbing any dividend already declared. —Ea: parts Williams, Re Kit Hill Tunnel, L.R. 16 Ch. D. 590; 50 L.J. Ch. 303; 29 W.R. 419.
Ch. Div. V. C. M.—Winding.up volu.nlarily—No liquidator Appointed —Distrcss.—On July 30th a company passed a resolution for a voluntary winding-up, but appointed no liquidators. The landlord of the company distraiued for rent. On August 9th liquidators were appointed, and on the 18th a compulsory order for windingmp was made: Held that the
distress was validly levied.—-Thomas v. Patent Lionits Jlfannfaclm-|"ng Co., 4»! L.T. 94; 29 W.R. 349.
County Court =—
(Y-)
(vi.)
Q. B, DiV.—Admiralty J'uris(licti0n—Action in rem for Necessaries— 31 5/‘ 82 Vict., c. 71, s. 2.—A County Court exercising Admiralty jurisdiction under County Courts Admiralty Jurisdiction Act, 1868, cannot entertain a claim for necessaries against a British ship, whose owner is domiciled in Great Britain.—Allen v. Gnrbull, L.R. 6 Q.B.D. 165; 50 L.J. QB. 14!; 29 W.R. 287.
C_ A_—(‘nnh-nl m-or by High Cou.rt—l\'oles by Jmlge—-Sig1n'ng Nolcs— 38 39 Vict., c. 50, s. 6.-—Decision of Q.B. Div. (see County Court iii., p. 52) nllirmed.—Morgan v. Rees, 414- L.T. 133 ; 29 W.R. 345.
§’ 20 Vict., c. 108, s. 26—Ord. 55.—The costs of an action remitted by the Superior Court to the County Court for trial, under 19 & 20 Vict., e. 108, s. 26,
are not within the jurisdiction of the County Conrt.—Fa/rmer v. May, 50 L.J. C.P. 295; 44- L.T. 148.
(see Crimes and Ofences vii., p. 53) aflirmed.-Latter v. Bradd-ell, 29 W.R. 366. C. C. R.—Bigamy—Presumption of Duration of Life.-—In 1861 W. married A. In 1868 he was convicted of bigamy for marrying B., A. being then alive. In 1879 he married C., and in 1880, C. being then alive, he married D. On a charge of bigamy for marrying D., 0. being then alive: Held that the question should have been left to the jury whether A. was not alive when W. married 0., as, if so, the marriage with C. would be invalid.—Regina v. Willshire, L.R. 6 Q.B.D. 366; 44 L.T. 222; 29 W.R. 473.
c. 75, s. 91.—G. was convicted on an information charging him with having been guilty of corrupt practices at a school board election “contrary to the sub-section of sec. 91 of the Elementary Education Act, 1870:" Held that the conviction was bad, as the ofience ought to have been specified and the time and place mentioned in the information. —Reg1'na v. Ingall, 29 W.R. 288.
Q. B. DiV.—Elementa/ry Education Acts— Attendance Orcler—Scho0l Fees—33 &3t Vicl.,c. 75, s. 17; 39 J” 40 Vict., c 79, 3.9. 10-12.—A parent who. under an order bya court of summary jurisdiction that his child shall attend a board school and that he do see the order complied with, causes the child to attend the school but without paying the school fees, is not liable to conviction under sec. 12 of the Elementary
Education Act, 1876, for non-compliance with the order.—Richardson v.
Saunders, L.R. 6 Q.B.D. 313.
Ch. Div. F. J'.—-Forcible Ent-ry—Occupier Holding Ouer—-Da,magos— 5 Ric. II.,[c. 1, s. 8.--Where an occupier unlawfully holds possession of a house against the rightful owner, and the owner forcibly enters and ejects the occupier, although the occupier cannot claim damages in respect of the forcible entry, he can for independent wrongful acts done at the
Q. B. DiV.—Malici0us Proxecuti0n—Prose/:uti0n by Police of Railway Company.—An action was brought against a railway company for malicious prosecution, plaintifi having been prosecuted by the police of the company: Held that such action would lie._—Edwa/rcls v. Midland Rail. Co., L.R. 6 Q.B.D. 287; 50 L.J. Q.B. 281; 43 L.T. 694-.
C. A.—Parlia.menta;ry Oath--Right to Aflirm—Penalty—Inf0rmer—29 ‘S’ 30 Vict., c. 19; 32 & 33 Vict., c. 68.—It is no defence to an action for a penalty for having sat and voted in the House of Commons without having taken the oath, that the defendant was a person npou whose conscience an oath had no binding effect, and that he had, before sitting and voting, made a solemn affirmation. The penalty imposed by sec. 5 of Parliamentary Oaths Act, 1866, may be sued for by a common iuformer.—Clarke v. Bmdlaugh, 29 W.R. 516.
Debtor and Creditor :
Ch. Div. V. C. B.—Attachment of Debt—Second Mortgagee—Sale by First Mor!ga5n'e.~P1u'orities.~A judgment creditor of a second mortgagee who has obtained a garnishee order against the mortgagor is not entitled to the surplus proceeds of the mortgaged estate when sold by the first
mortgagee under his power of sale after the date of the order. But the holder of a garnishee order against the first mortgagee, it having been obtained after the sale, is entitled to attach the nrplus proceeds in the hands of the first mortga-gee.—-Ohatte-rton v. Wat/ney, L.R. 16 Ch. D. 378; 50 L.J. Ch. 227; 44 L.T. 53; 29 W.R. 378.
C. P. Div. Execution — Compositz'011——Failu/re to withdra-w SlwnEj'.—ln the absence of malice no action will lie against a judgment creditor for not withdrawing the sheriff from possession after the creditor has become bound by a composition of the debt.—Plu'l-lips v. General Omnibus Co., 50 LJ. C.P. 112.
Q- B. DiV.——Judg1nent Summons— Ga/rnishea Order—Oonc1u-rent Revue. dies.—A judgment creditor obtained an order for the examination of the debtor, with a view to ascertaining whether any debts were due to him. The debtor failed to appear, and the creditor obtained a judgment summons by which the debtor was ordered to pay the amount of the debt by instalments: Held that having obtained this order he was not entitled to an order for the debtor's attachment for not appearing for examiuation.—Hayton v. Beall, 44 L.T. 131 ; 29 W.R. 333.
Ch- Div. V. C. B.—~Prics of O_fiicer’s Com'missian-—1ncu/mbi-a.ncers— Notice—Priorily.—'l‘he incumbrancer who gives notice to the army agents who have received the money paid by the Army Purchase Commissioners for an ofiicer's commission, first after the publication in the Gazette announcing the officer's retirement, will have priority; and where several give notice simultaneously, they will rank according to the seniority in date of the instruments creating their incumbrances.—
:_P.C.—SZa'nder—Inue'ndo—Dou.btfulMeaning.—In an action for slander, if the declaration contains inuendoes, a plaintifi cannot substitute for them a prefatory averment in the same declaration imputing motives to defendant. If the words complained of have two meanings, one imputing suspicion, and the other guilt, the question in which sense they were used is one for the jury, and a witness to whom the words were addressed cannot be asked in what sense he understood them.—Simmons v. Mitchell, L.R.6App. 156; 50 L.J.P.C. 11; 43 L.T. 7l0; 29 W.R. 401.
(‘om-1m'ftee.—A witness examined before a Committee of- one of the Houses of Parliament is absolutely privileged as to anything he may
special case stated in an action for damages for wrongful entry, the Court was equally divided in opinion as to whether a grant of a right of way over the grantor’s land was limited to the use of the way for the special purposes expressed in the grant, or whether it gave an unqualified right of way.—Sm1mcr v. Sr/hofield, 43 L.T. 763.
joining.-—Whcre the owner of a house and adjoining land sells the house
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Takedown: Inside the Hunt for Al Qaeda
Philip Mudd
University of Pennsylvania Press, Mar 22, 2013 - Political Science - 216 pages
On September 11, 2001, as Central Intelligence Agency analyst Philip Mudd rushed out of the Eisenhower Executive Office Building next to the White House, he could not anticipate how far the terror unleashed that day would change the world of intelligence and his life as a CIA officer. For the previous fifteen years, his role had been to interpret raw intelligence and report his findings to national security decision makers. But within weeks of the 9/11 attacks, he would be on a military aircraft, flying over the Hindu Kush mountains, en route to Afghanistan as part of the U.S. government's effort to support the fledging government there after U.S. forces had toppled the Taliban. Later, Mudd would be appointed deputy director of the CIA's rapidly expanding Counterterrorist Center and then senior intelligence adviser at the FBI. A first-person account of Mudd's role in two organizations that changed dramatically after 9/11, Takedown sheds light on the inner workings of the intelligence community during the global counterterror campaign.
Here Mudd tells how the Al Qaeda threat looked to CIA and FBI professionals as the focus shifted from a core Al Qaeda leadership to the rise of Al Qaeda-affiliated groups and homegrown violent extremism from Europe, the Middle East, and Asia. As a participant in and a witness to key strategic initiatives—including the hunt for Osama bin Laden and efforts to displace the Taliban—Mudd offers an insider's perspective on the relationships between the White House, the State Department, and national security agencies before and after the invasions of Iraq and Afghanistan. Through telling vignettes, Mudd reveals how intelligence analysts understood and evaluated potential dangers and communicated them to political leaders.
Takedown is a gripping narrative of tracking terrorism during what may be the most exhilarating but trying times the American intelligence community has ever experienced.
You have reached your viewing limit for this book.
1 The 911 Aftermath
2 A Return to Langley
Moving Beyond the Core of Al Qaeda
The Intelligence Problem of Iraq
Deputy Director of the Counterterrorist Center
6 The Years of Threat
The FBI Calls
Intelligence at the Department of Homeland Security
afghan afghanistan agency agency’s al Qaeda analysts answer asked attacks ayman al-Zawahiri briefer briefing Bureau bureaucracy cells CIa’s COMPSTaT Congress congressional conversation core counterterror campaign Counterterrorist Center decade diplomatic director Dobbins early example executive field offices fight focus foreign global intel intelligence investigation Iraq Islamist issues Jemaah Islamiyah Kabul Karzai knew later law enforcement leaders leadership ligence looking managers meeting military mission morning move national Counterterrorism Center national security never northern alliance ofthe ofwhat operations organization overseas Pakistan Pashtun piece players plots plotters policymakers polygraph president problem Qaeda questions quickly recruit remember reports response Saddam security services seemed senior sense significant simply speech staff story suicide bombers takedown Taliban talk targets Tenet terrorism terrorist thought threat information threat matrix U.S. government understand United wanted washington wasn’t watching white house Zawahiri
Philip Mudd served as Deputy Director of the Counterterrorist Center at the Central Intelligence Agency and later as Deputy Director of the National Security Branch at the Federal Bureau of Investigation. He is an independent consultant and a Research Fellow at the New America Foundation.
Title Takedown: Inside the Hunt for Al Qaeda
UPCC book collections on Project MUSE
Author Philip Mudd
Publisher University of Pennsylvania Press, 2013
Political Science / Terrorism
Technology & Engineering / Military Science
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Beheaded on the Road to Nationhood: Sarawak Reclaimed—Part II
Robert Raymer with Ernesto Kalum as Retap and Iban war party
After being beheaded as Alan Lee in the documentary Road to Nationhood: Sarawak Reclaimed by Rentap and his war party, my head didn’t hurt, nor was there any swelling, but I could really feel the pain in my ribs that night—I must’ve bruised or cracked one when I fell several times while being killed—which made it difficult for me to sleep.
Back in my twenties, I cracked a couple of ribs after getting kicked in taekwondo, so I knew there wasn’t a whole lot a doctor could do except X-ray it for confirmation and give you something for the pain. They used to wrap your chest but they stopped doing that decades ago. The pain was manageable; it only hurt when I laughed or slept or rose from sitting, so I opted not to see a doctor, but I did need to repair my black leather shoes. Maybe from all of the falling or banging it on the short steps at the Iban Longhouse, the sole in front started to come off.
Since I was not needed until Saturday, my big day where I was to play several characters—the Governor of Singapore; John Brooke, who had been passed over in favour of Charles Brooke as the second White Rajah; and the younger version of Captain Henry Keppel, a British naval officer who had served in the Opium War and assisted the first White Rajah James Brooke’s campaign against the Borneo pirates and Iban warriors—I had plenty of time to find a shoe cobbler to fix the problem.
Throughout the day, I kept receiving photos of the shoot being posted on the WhatsApp Group. Some made me pause and wonder because they looked like my scenes. I knew there had been some changes on the shooting schedule, so I double checked Friday’s call sheet to make sure my name was not on it. I thought, perhaps, I had overlooked it.
Late that afternoon, I got a message from Mark to confirm that I needed transportation for Saturday. Then two hours later, Prisca contacted me and asked if I could drive out to the Sarawak Cultural Village on my own. Seems there was a problem with the tide for the boat scene and they needed to start shooting a lot sooner than planned. I needed to be there by 6:30 am, which meant I had to get up at 4:30 am if I wanted to make the 50 km journey from my house on time.
My wife told me to take a new shortcut to Damai, via Pending, the opposite way we normally took, via Satok; both would head north on the other side of the Sarawak River. Last night it had rained and was still drizzling when I arrived at the Bidayuh Longhouse, the new base of operations at exactly 6:30 am—without getting lost, surprising my wife.
Alex and Charles Rentap (real name!)
I was told that all of the afternoon shoots had been cancelled, confirming my suspicions. Since yesterday, Friday, was a public holiday, the staff would not be around at the Bishop’s House, so they decided to create the shots they needed at the Sarawak Cultural Village using two other Caucasians, the Fort Guards, Alex and Charles for the Governor of Singapore and John Brooke.
Malaysia and Sarawak flags
Swapping roles at the last minute was quite common. Sometimes, someone couldn’t make it for the shoot, so they would grab whoever else was handy; others, as requested, sent a replacement for themselves. Jimmy, one of the extras, told me that he played nine roles. A little makeup, a change of costume, and he could pass for one race or another. Others played at least five or six roles, one or two primary, up-close shots, and the rest secondary to fill out the numbers.
For the battle scenes, which took place last night, they made about a dozen people look like a hundred, taking multiple close-up shots from different angles, catching various parts of their bodies. Those working on the actual footage reported how impressed they were seeing it on film.
After we were dressed in our costumes, they drove Alex, who was to portray the 14-year-old Charles Brooke, and me, as the younger Captain Henry Keppel, to a nearby jetty in Santubong where we boarded a fishing boat with a trimmed down crew. Altogether, including the director, Fendi, and Rob, there might have been eight or nine of us. Since it looked like it was going to pour anytime soon, we were all in a rush to get set up and to start filming.
Fendi, the Director
They had Alex and me stand at the bow, looking off toward our left, with the camera positioned behind us, shooting us, the sea and the blackening sky assuring us that a storm was approaching.
While filming, I explained to the young Charles Brooke, the future second White Rajah of Sarawak that someday, all of this would be his….It was Charles Brooke who greatly expanded the territory of Sarawak beyond the original city of Kuching to its present borders.
Luckily for me, I wore a hat when it began to drizzle; unluckily, the British flag that they had mounted kept pushing at the back of my head nearly knocking the hat off before they tied the flag down.
To get the angle they were looking for, we had to kneel on the deck, with our backs erect. The position was uncomfortable, so we were glad when the director suggested that we remove our shoes, which helped.
Later, when it began to rain heavily after the shooting, as I was rushing for cover, the hat flew off my head, but I somehow managed to catch it midair before it was lost forever at sea.
Author Robert Raymer and Rob Nevis, Executive Producer
I had planned to get some shots of the fishing boat that we had used but the heavy rain prevented me from doing so; I wished I had taken the shots before boarding but we were in a rush to beat the rain....Alex and I returned to the Bidayuh Longhouse, while the others stayed behind to shoot more river footage.
They then spend the rest of the day and the following day taking B-roll shots—outtakes without actors—at notable sites such as Fort Margherita, the Istana, the Courthouse, and other historical buildings, and the surrounding environs to work into the documentary.
The A-roll shots are the main scenes with the actors and extras, the most costly part of the filming, which is why they try to cram it all into several long days for documentaries or a few intense weeks for feature films.
Rob Nevis and Jason Brooke
Before leaving Kuching, Rob managed to have tea with Jason Brooke, grandson of the last Rajah Muda of Sarawak.
Even though the rescheduling of the shoot made me miss out on some important scenes, including having a private tea with James Brooke as the Governor of Singapore, no doubt suggesting that he seek his fortune in Borneo, I was quite happy to keep my head about me at all times, just in case someone decided to, well, you know, this is land of the headhunters, and that Iban war party did kill me in that other scene…
It was also quite an honor to be a part of recreating history—an honor for all of us involved from the cast, the crew and production—in the Road to Nationhood: Sarawak Reclaimed.
Beheaded on the Road to Nationhood—Part II
Joseph Conrad and Me
Somerset Maugham and Me—Part I-V
See the trailers: https://borneoexpatwriter.blogspot.com/2018/10/road-to-nationhood-sarawak.html
Road to Nationhood: Journey to Independence part I (1945-1957)
Road to Nationhood: Journey to Independence part II (1957-1965)
Posted by Borneo Expat Writer at 11:23 PM No comments:
Labels: Borneo history, Charles Brooke, Fendi, Henry Keppel, Iban, James Brooke, Kayu Malam Productions, Rack Focus Films, Road to Nationhood, Rob Nevis, Sarawak, Sarawak Cultural Village, Sarawak history, White Rajah
Beheaded on the Road to Nationhood: Sarawak Reclaimed—Part I
Robert Raymer and actors, Road to Nationhood: Sarawak Reclaimed
Last year I was in a French documentary discussing Somerset Maugham in Sarawak, but this year I found myself getting beheaded in the Malaysian documentary Road to Nationhood: Sarawak Reclaimed. The documentary, a Rack Focus Films production, is the Third Season in the highly successful Road to Nationhood series, and originally scheduled to be aired 16 September 2018—on Malaysia National Day—on the National Geographic channel, Astro. Because of some unexpected delays, it would more likely be aired sometime in October.
Malaysia was formed when Singapore, North Borneo (Sabah) and the Sarawak Crown Colonies joined the Federation of Malaya on 16 September, 1963; however, two years later, Singapore separated to become an independent republic.
Thirty years later, I was an extra in several notable Hollywood films, such an Anna and the King, Paradise Road, Beyond Rangoon, and the French film Indochine. It was on the set of Indochine—Oscar winner in 1993 for Best Foreign Language Film plus an Oscar nomination for Catherine Deneuve for Best Actress—where I met Rob Nevis
Christmas Party scene, Indochine
Catherine Deneuve and Linh Dan Pham, Indochine
Rob Nevis, center, on the set of Paradise Road
Back then, Rob worked with Film Location Services, but now he was a producer with Rack Focus Films. A few months ago, Rob and I met in Kuching where he told me about the project and asked if I would be interested to take on a role, possibly Charles Brooke, the second of three White Rajahs—who ruled Sarawak for one hundred years from 1841 to 1946.
Charles Brooke and author
James Brooke
The first White Rajah was an Englishman James Brooke. After helping the Sultanate of Brunei fight piracy and an insurgency among the Dayaks, he was rewarded the city of Kuching. The third and last White Rajah, Charles Vyner Brooke, was mostly an absentee ruler. Following the Japanese Occupation, he controversially ceded Sarawak to Great Britain at a time when they were shedding their British Empire.
Giovanni and Ivan at center
Giovanni as James Brooke
After finding Ivan, a Hungarian friend who is more muscular and younger, to play Charles Brooke, and Giovanni, an Italian who is taller and younger to play James Brooke, I was asked to portray various colonial officers and officials. My first role would be Alan Lee, a colonial officer, who unfortunately was killed during a battle with Rentap’s Iban warriors.
Alan Lee’s beheading proved to be a turning point in the Rajah Brooke’s determination to capture or kill Rentap (which he never did—his famous translated quote was “still alive, still fighting”) and defeat the Saribas and Skrang Ibans, notorious headhunters who routinely attacked Bidayuh settlements throughout Sarawak including Quop, where my wife is from—decimating the population.
Several days before filming began the cast were called to Kayu Malam Productions, opposite of Crown Square, for wardrobe fitting and briefing by the director, Fendi, and Rob, our executive producer. This was the first time that the Kuching group would be meeting the Kuala Lumpur group (Rack Focus Production) and those they brought in from KL to assist them, like Johnny Goh, Prop Master.
Bani making adjustments
Johnny Goh and Rob Nevis
Bani, Wardrobe
Bani, in charge of Wardrobe, separated us by groups: Iban warriors, Chinese miners, Istana people, Malay extras, and a handful of Caucasians portraying Colonial Officers, Captains and Fort Guards. We took photos of one another in various costumes. The heavy wool coat that I tried on looked good; however, it was a little long in the sleeve and rather impractical for the tropical Sarawak climate.
Robert and Giovanni
During the briefing we were told that, unlike feature films, the budget for documentaries was minuscule, so compromises had to be made—there wouldn’t be endless takes from all angles. Also Season Three of the series would be the most difficult to film. Road to Nationhood: Journey to Independence Part I (1945-1957) and Part II (1957-1965) in Season One were largely made from historical archives, but since there were very little archives for early Sarawak, scenes had to be re-enacted, hence the need for actors and extras. I was told we would not be speaking (only perceived to be speaking or having a discussion) while a narrator pointed out the historical significance of what was being viewed.
Filming was originally scheduled to begin near the end of July but had to be pushed back a month because the production permits for filming in Sarawak were held up. The French crew had the same problem. For this project, it would be a big problem, which meant the time for post-production was being compressed. The moment all of the footage was shot for a particular scene, it had to be sent, without delay, to post production to work on and be pieced into the documentary. Unfortunately, films or documentaries were rarely, if ever, shot sequentially.
Jimmy, one of the extras, set up a WhatsApp Group so we would all be in the loop, which made it easier for Prisca, Unit Production Manager, to find someone, or for Mark, Transport Manager, to clarify who needed transportation to Sarawak Cultural Village, where most of the shooting would take place.
Prisca and escorts
Although shooting began on 28 August 2018, I wasn’t called in until two days later on Thursday, 30 August, for my first scene. Thanks to all of the photos from the shooting posted on the WhatsApp Group by Jimmy, Prisca and others, I could keep up with the filming. Since it was a relatively small cast, about 30 of us, with everyone playing multiple roles, I recognized many of the faces from our previous meeting.
We were told to be at Kayu Malam Productions by 7 am, so I was up at 5 am to avoid all of the school traffic. En route to Damai, three otters ran across the road in front of our van, which I took as a good sign. Not long after we arrived at the Iban Longhouse in the Sarawak Cultural Village, our base of operations, Bani and Sheila from Wardrobe outfitted the Iban Warriors and then the makeup crew and the tattoo specialist led by Dedek, got to work, creating some elaborate Borneo tattoo patterns all over their bodies including the exposed parts on their upper thighs and buttocks. Others tried on wigs.
As we sat there waiting for our turn, extras in their respective native outfits would walk by carrying shields and spears and swords or rifles. All of the Chinese characters, I noticed from the photos taken on the first two days, had the front half of their heads shaved and a long queue added to their hair, fitting the Manchu style back in the 1840’s. Some of the Ibans had their hair cut as if someone had used a bowl; more likely they were wearing wigs.
Johnny showed me my head that he made and asked, “Does this look familiar?”
At the briefing we were told to expect a lot of waiting, something I had experienced on previous productions. I had brought a book; however, I mostly talked with others in the cast and the crew, getting to know them. We were also free to roam around the set and watch other scenes being shot, which I gladly did.
Ivan Evetovics as Charles Brooke
“Can you see the camera?” the director called out to Ivan, who was portraying Charles Brooke, surrounded by extras. “If you can see the camera, then the camera can see you.”
During the previous meeting, I met the actor who would portray Rentap, the leader of the Skrang Ibans, who was quite large like the real Rentap, but then he was replaced by Ernesto Kalum, a world-renown tattoo specialist with a London law degree, who looked a whole lot more fierce….Later, when I was introduced to Ernesto on the set, I was told, “This is the man who is going to behead you.”
Ernesto Kalum as Rentap
I was unaware that my scene was a night shoot, so I could’ve come a lot later. Several others like me had to wait all day long, not that we minded….Twelve hours would pass before I was finally asked to get into my costume—white shirt, blue trousers, gray cap. I was asked to bring my own black leather shoes, which I did. Giovanni forgot, so they had to cut a new pair of shoes in back for his size 13 feet.
Although we were supposed to finish the day at 9:00 pm we didn’t finish shooting until 10:30 pm. While waiting for the other scenes to finish, I posed for a few shots with Rentap and his Iban war party before they had a chance to behead me.
I could see the fort area where I would be killed.
Then I heard Fendi, our director, call out, “Bring the dying man.”
He was referring to me, but it sounded like I had some incurable disease….In position, we watched the Iban war party approach the makeshift fort. One of the Fort Guards, Alex appeared, but then he went one way while the war party, who had been hiding, went the other. Before I was called in to be killed, they gave one of the warriors, Watt, a real Iban sword, and they had him swing down hard on what appeared to be a coconut, as if he were chopping off my head. Once that segment was completed, they switched out the real sword for one made of plastic.
Watt and wife (real)
When it was my turn to come on, I removed my glasses, which made it difficult to see. Previously, I wore contacts. The director told me to ditch my hat, so I tossed it aside. Meanwhile someone marked my position in front of the camera with an upturned leaf that I could not see without my glasses. All the leaves seemed to blend in together, plus it was dark outside. An assistant and the cameraman kept telling me to stop “here” at a particular leaf for a close up shot of my being killed. Without my glasses I couldn’t quite see which particular leaf they were pointing to. For a close-up shot, an inch here or there made a huge difference.
“What seems to be the problem?” asked the director, and someone explained that I couldn’t see the leaf without my glasses.
Finally someone set down a white folder just out of camera range and told me to stop just before the folder. No problem, I could see that. The director then asked me to breathe heavily as if I feared for my life. I was to stop at my spot, pivot, look right and then left….We ran through the sequence several times. When I turned to look right, and then left, the Iban warrior would come up from behind me and bring down his sword.
Before the actual filming began, I approached Watt and felt the sword to make sure he did in fact switch them, prompting laughs from everyone watching, about twenty-five people including the extras and technicians. I definitely didn’t want any untoward mishaps involving my head.
The first run through, Watt clipped my ear with his sword and it stung a little. He duly apologized.
Fendi asked me to fall to the ground the moment I got hit, which I did. I thought I was pretty convincing. Maybe too convincing because it suddenly hurt around the ribs; I must’ve landed on my elbow while trying to protect my glasses secured in a pouch inside my shirt, not wanting to crush it. We did two or three more takes and the last one, Watt got me pretty good on the side of the head. It sounded really loud. There was this startled hush when I collapsed as if I really had been killed. I stayed down a long time for dramatic effect, thinking perhaps Watt was a little too realistic on that last one, hoping there would be no more takes, not sure how many more blows my head could take.
This is not me, but you get the idea.
When the director called, “Cut!” everyone, no doubt, thought I really did get cut by that sword. They all heard the impact on my head and saw me drop dead, again rather convincing if I don’t say so myself. Watt kept apologizing profusely. He told me he couldn’t stop the momentum of his swing in time. Luckily he was not using a real sword or I would not be writing this.
Several people rushed over to make sure I was in fact okay. I kept assuring them I was fine.
“See, no blood,” I said.
The blood would come next. Not mine, but the blood mixture meant for my substitute head. The director took a closer look at that head. Although the face did look like me, they got the hair wrong. I tried to point it out earlier to Johnny before they attached the hair, but he assured me that the thick black hair didn’t matter because it would soon be covered with blood. Still, I thought, it looked way too thick—blood or no blood.
The director didn’t like the way-too-thick black hair either and asked if it could be cut from the head. Then they decided not to use the head in that scene, since it was pretty obvious when Watt got me the last time, he had severed my head. Not wanting to waste the head and the blood that they were applying, someone suggested it could be used for a scene with a crocodile at a nearby swamp. So they carried away my former head and covered it with more blood and filmed it by the swamp.
In a later scene, Iban warriors were seen carrying away their heads in makeshift rattan holders.
As for me, as I walked off the set, I carried my own head exactly where it belonged—on top of my shoulders.
Beheaded on Road to Nationhood: Sarawak Reclaimed—Part II
Road to Nationhood: Journey to Independence part I(1945-1957)
Posted by Borneo Expat Writer at 1:58 AM No comments:
Labels: Borneo tattoo, Charles Brooke, Ernesto Kalum, Iban, Indochine, Kayu Malam Productions, Rack Focus Films, Rentap, Road to Nationhood, Rob Nevis, Sarawak, Sarawak Cultural Village, Sarawak history, White Rajah
Beheaded on the Road to Nationhood: Sarawak Reclai...
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Best in Show: 2019 Geneva Motor Show
Home/Blog/Best in Show: 2019 Geneva Motor Show
Fifth Place: Koenigsegg Jesko (16 Points)
Associate Editor Joel Stocksdale: It’s such a gloriously absurd car. It uses a tank of compressed air to keep the turbos spooled up. It has potentially the biggest wing ever on a production car. It has an analog G-meter. It has a transmission that can shift to any gear as fast as a DCT can go up or down one. It’s a monument of wild technology and design, and one that really exists and works, which is why it’s my pick of the show.
Assistant Editor Zac Palmer: Adding gears to a transmission is clearly old news at this point. Turns out, we should’ve been adding clutches all along, like the seven-clutch transmission in the Jesko. Who knew? In all seriousness, though, this supercar is definitely the king of the supercar show.
Fourth Place (tie): Honda e Prototype (19 Points)
Senior Editor Alex Kierstein: Honda, if you have any love for us Americans, find a way to sell this car here. Lose some money on it if you need to. It’s got an unbelievably charismatic appeal – although the contrasting charge door panel simply doesn’t work for me. Easy enough to fix, though.
Road Test Editor Reese Counts: Yes, it’s not yet a production model, but it’s inching even closer to what you’ll eventually find on European streets. It looks fantastic, with just enough retro flair to make it interesting. Too bad we won’t get it in America. I’d love to see an all-electric Si or Type R variant down the line.
Fourth Place (tie): Pininfarina Battista (19 Points)
Consumer Editor Jeremy Korzeniewski: It’s got Ferrari-esque good looks, but what I’m really stoked about is the 1,900-horsepower all-electric, all-wheel drive powertrain.
Road Test Editor Reese Counts: How can you not vote for this thing? It’s quicker to 60 mph than a Formula One car, makes a comical amount of horsepower and packs in all the design flair you expect from something out of Pininfarina. Plus, it puts out zero emissions thanks to its Rimac-supplied powertrain. Sure, it would sound great with a V8 or V12, but the world has enough of those already.
Third Place: Polestar 2 (22 Points)
Senior Editor, Green, John Snyder: Best in show, if you ask me. Absolutely stunning, wonderful electric performance, and it’s something I could potentially afford? Nobody does this.
Associate Editor Joel Stocksdale: It looks amazing with killer performance to boot. I wish it was cheaper, but you’ll be getting a lot of car for the money. It will be exciting to see comparisons of this, the high-po Teslas and the Jaguar I-Pace.
Second Place: 2020 Mercedes-Benz CLA Shooting Brake (24 Points)
West Coast Editor James Riswick: It’s a yellow manual wagon. It’ll never be sold here, so the only thing to do now is ask if I can do my job from Holland.
Social Media Manager Michael Dylan Ferrara: If I lived in Europe this one would be no brainer “Take my money.” First of all, wagons are the best, and secondly, would you look at that yellow paint and the interior accents? Love it. It’ so disappointing we won’t be getting this in the States.
Editor-in-Chief Greg Migliore: This is the car I’d most like to drive off the show floor and use to wander across Europe with wine and cheese in the cargo hold.
First Place: VW I.D. Buggy Concept (30 Points)
Editor-in-Chief Greg Migliore: Easily the most fun, fanciful car in Geneva. Buggies are exuberant and VW got the styling just right, capturing the emotion and feel of a bygone era. The EV powertrain makes it realistic for modern times.
Consumer Editor Jeremy Korzeniewski: As much as I’d love to see this thing sharing space in VW dealerships with the I.D. Buzz electric van, I just can’t see that happening. Regardless, VW gets credit for building and showing the thing in Geneva, and I fully expect someone to take ’em up on the idea to experiment with an electric buggy built off the MEB platform. Last question: How long until we see an MEB-based Thing?
Senior Editor Alex Kierstein: This may not ever make it to market, but the idea of a green vehicle purely made for fun is really exciting. It’s a nice design, obviously inspired by the old Manx buggies but not a pure retro play, and perhaps the most handsome of all the I.D. designs so far. Let’s hope VW builds it, even if only as a loss leader to draw attention to the I.D. range.
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NEWS: Boulder Creek Highway 9 Pedestrian Crossings to be Updated
December 20, 2018 By JD in News Tags: basic life skills 3 Comments
9 and Forest Street in Boulder Creek 9 and Pool Drive in Boulder Creek are going to be getting “a combination of treatments, including installation of high-visibility striping and signage, advance warning flashing beacons, and Rectangular Rapid Flash Beacons.”
Press release from the Santa Cruz County Regional Transportation Commission (RTC) is below…..
RTC Receives Highway Safety Improvement Program Grant for
Highway 9 Pedestrian Crossings
The Santa Cruz County Regional Transportation Commission (RTC) received $250,000 in grant money from the California Department of Transportation (Caltrans) Highway Safety Improvement Program (HSIP) for pedestrian crossing safety projects on Highway 9 (State Route 9/SR9) in the San Lorenzo Valley.
SR9 serves as a main thoroughfare for pedestrians to access schools, libraries, parks, commercial areas and homes. There are only four signal lights and one stop sign on the highway, and many of the intersections that pedestrians regularly use for crossings have no safety controls.
RTC staff, working with Caltrans, the County of Santa Cruz Public Works Department, and community leaders, identified five intersections on SR9 with high foot traffic and high pedestrian involved collision rates where the installation of pedestrian crossings with enhanced safety features should be prioritized.
The intersections where pedestrian crossings will be improved with the HSIP grant money are:
SR9/Redwood Drive in Felton;
SR9 midblock crossing between Graham Hill Road and Kirby Street in Felton;
SR9/Clear Creek Road in Brookdale;
SR9/Forest Street in Boulder Creek; and
SR9/Pool Drive in Boulder Creek.
Improvements at these five locations vary and will include a combination of treatments, including installation of high-visibility striping and signage, advance warning flashing beacons, and Rectangular Rapid Flash Beacons.
Enhancements in these key locations will improve crossing safety for pedestrians and bicyclists by alerting on-coming vehicles of the presence of a lawful crosswalk and/or that the crosswalk is occupied.
“The heavily used pedestrian routes along Highway 9 have a history of motorist and pedestrian collisions. These crosswalk improvements will increase visibility of the crosswalks and pedestrians, alerting motorists to their presence and warning motorists to slow down near crossing locations,” said Santa Cruz County Supervisor Bruce McPherson, whose supervisorial district covers the San Lorenzo Valley. “Pedestrians will have safer access to transit stops, parks, neighborhoods, businesses and other services they rely on in this rural area.”
According to data from the Transportation Injury Mapping System, there were 34 pedestrian involved incidents on SR9 from 2006-2017. Twenty-three of these incidents, including three pedestrian fatalities and four pedestrian severe injuries, occurred at an intersection where the pedestrian had the right-of-way, and in 15 of these incidents, the pedestrian was crossing in a marked crosswalk.
The RTC is currently working on the SR9/San Lorenzo Valley Complete Streets Corridor Plan, a planning study that provides a vision, guiding principles, and realistic strategies to improve how people get around San Lorenzo Valley. Data gathered during initial outreach for the plan shows that crossing SR9 is a priority safety issue for pedestrians and bicyclists. In early 2019, the RTC will gather community feedback on the draft Complete Streets Corridor Plan in order to prioritize implementation of a range of identified projects along the corridor.
For more information on the Caltrans’ Highway Safety Improvement Program, visit http://www.dot.ca.gov/hq/LocalPrograms/hsip.html.
« In Memoriam: Bobby Carr
Sherrif: Gun Arrest Made in Boulder Creek »
Steve Scarich says:
I have mixed feelings about these sorts of crossings. I assume when the ped shows on the display, a pedestrian thinks it is safe to cross. But, in Oregon, where I live, we have similar crossings, and sometimes drivers yield and sometimes they don’t, so it gives a false sense of security. In fact, in Oregon, a little box tells you that the light is flashing, but be aware that traffic may not stop. btw, I was born in BC in 1947 and still follow local events.
drhal2010 says:
Hooray! I’ve been asking about these improvements ever since participating in the the series of Boulder Creek traffic safety meetings a few years ago. All good things in time – sometimes. Hal Anjo, Boulder Creek
“Every day is extra” John Kerry
On Thu, Dec 20, 2018 at 2:27 PM Boulder Creek Insider wrote:
> JD posted: “9 and Forest Street in Boulder Creek 9 and Pool Drive in > Boulder Creek are going to be getting “a combination of treatments, > including installation of high-visibility striping and signage, advance > warning flashing beacons, and Rectangular Rapid Flash Beac” >
Michael Sorensen says:
In Boulder Creek they have a crosswalk at the stop sign. On the next block they have two crosswalks 20’ apart with no stop sign and vehicals park on both sides of this crosswalks blocking the view of about the first 8’ of each side of the crosswalks. I don’t care how many blinks lights they put on the road. I always watch to see if traffic is going to stop before I cross.
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New Machine Gun Kelly ‘Black Flag’ Mixtape [Free Download]
Machine Gun Kelly has something new for your ear holes. Black Flag is a carefully crafted mixtape that showcases why his sound has turned into a movement. Kells, as he is known by his fans, has been on the road furiously promoting his major label debuted Lace Up which debut at #4 on the Billboard T…
Projectus – HUSHUSH at Midnight Spotlight Artist [Listen]
Name: Projectus
Mike, aka Projectus, grew up in northwestern Montana after moving from Southern California when he was only 6 years old.
Chachi on hushush @ midnight tonight!
Name: Red Velvet
I moved to Bozeman a couple years ago. Bozeman opened my eyes up to the electronic music scene. I couldn't sit on the sidelines anymore. I wanted to get my hands dirty so i invested in some cdjays and a mixer and started the learning process. I am also realizing that with mixing you …
Name: Chachi
Hi it's Randy Leibenguth…aka Chachi… I'm a 34-year-old Montana native. In the late 90’s I began spinning hip-hop CD’s at a frat house at Montana State University in Bozeman. This is also where I got my nickname Chachi.
Tyga Feat. Game “Switch Lanes” [Music Video][Free Download]
Justin Timberlake's Suit and Tie has gained popularity too fast for me to only play the song once a day, so I'm picking a new one to finish out the week. YMCMB member Tyga hits the internets with visuals for his track "Switch Lanes" featuring Game...
Top 5 Albums To Look Forward To In 2013 Features Angel Haze [Music Video][Free Downloads]
While I was Stumbling this weekend I came across a list of "5 albums to get excited about in 2013" from a website called Mother Jones. Angel Haze is featured on the list. Angel has come into headlines in the last few months with her Twitter beef with Azealia Banks (another female M…
Big K.R.I.T – Thoughtful Voice Of Hip-Hop? [VIDEO][Free Download]
Big K.R.I.T. was a member of the XXL Freshman 10 of 2011. The annual list is interesting to watch as some of the picks blow up and take over the Hip-Hop spotlight. Others fizzle out. But sometimes you find one that just gets it. Big K.R.I.T. is that artist. Thought provoking, calm, real, and no…
Free Download From Chamberlin Showcase DJ/Producer, Feldman
This Friday, ten DJ/Producers will be showcasing their talent and mixes at the Zebra Cocktail Lounge to see who is the best DJ/Producer. What do we call this culmination of music mastery? It's the 2011 Chamberlin Showcase of course. Not only are DJ/Producers featured, on Saturday ten bands will be g…
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Free MP3 From HUSH HUSH Headliners ‘Beats Antique’
Beats Antique will be headlining a stellar lineup at the first ever HUSH HUSH festival this Saturday, September 24th, and we've got a free MP3 download for you to enjoy. Also check out the revealing of their album artwork for their upcoming album release in October.
HUSHUSH Band Profile And Free MP3 From Ebola Syndrome
Four days away from HUSH HUSH and we have another free download from one of the groups performing on Saturday September 24th. The duo out of Missoula promise to offer cutting edge electronic music as they deliver soulful hip hop, heavy dubstep with blistering drum and bass...
Pre HUSHUSH Sub Swara Free MP3 Download
Sub Swara's most recent track (2 days old!) was featured on the international blog NADA:BRAHMA that aims at featuring only the best music from around the world. Guess what, Sub Swara will be live at HUSH HUSH this weekend in Bozeman. Download the free MP3 of Sub Swara's newest track On The…
Eminem And Royce The 5’9″ EP Release Date, [Free Mix Tape Download]
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MSU Hockey To Be Shown On SWX Montana
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Theater Review: ‘Dreamgirls’ Is Kaleidoscope of Talent
By J.E. Ballantyne Jr.
YOUNGSTOWN, Ohio – The Youngstown Playhouse first produced the musical Dreamgirls in 1989. Judging from the enthusiastic response from the opening night audience Saturday at the current Dreamgirls production at the Playhouse,“absence does make the heart grow fonder.”
With book & lyrics by Tom Eyen and music by Henry Krieger, the high energy musical received an avalanche of love from a sold-out audience.
The show tells the story of the rise to fame of a fictional girl group known as the Dreams laid against the background of such acts as The Supremes, The Shirelles, James Brown, Jackie Wilson and the birth of the Motown sound. The original Broadway show was nominated for 13 Tony Awards and walked away with six winners.
There is no question that the Playhouse production is a winner. An insanely talented cast cranks out the high energy story with such an even and fast pace that there is hardly time for audience applause from one musical number to the next.
Playing the intense role of Effie White, lead singer of The Dreamettes (before they become The Dreams), is Cleveland actress Sharleen Riley.
This role is no stranger to Riley who previously played it at the Akron Civic Theatre. That familiarity paid dividends to her as she was totally immersed in Effie from her first appearance at the Apollo Theatre in Act I to the final Dreams appearance in New York in Act II.
Sharleen Riley is totally immersed in her role as Effie.
Riley is a powerful presence on stage and commands attention in every facet of her performance. She literally stops the show with her Act I closer, “And I’m Telling You I’m Not Going.”
Her cohorts in music Jennifer Zamis (as Deena) and Arielle T. Green (as Lorrell), both shine particularly when Effie is ousted from the group and Deena takes over her lead vocals. Zamis and Green show considerable depth in their characters as their lives change and the group dynamic of The Dreams changes during their rocky road to stardom.
The new Dream addition of Myra Corley (as Michelle) does herself proud in her theatrical debut and shows a lot of promise for future productions.
As Curtis Taylor, Jr., the manager for The Dreams, Joshua William Green gives a strong performance and is a perfect buffer for Effie. A very talented actor, Green breathes total believability into his character and his scenes with Effie are sharp and powerful as the no nonsense manager pulling The Dreams’ strings.
Curtis Taylor Jr. is played by Joshua William Green.
James Major Burns turns in a masterful performance as James Thunder Early, a James Brown-esque character. Burns carries a lot of the comedy load in the show and doesn’t miss a beat.
James Major Burns portrays James Thunder Early
Karrington Griffin and Martin Charles as C.C. White and Marty, respectively, offer up strong performances in smaller roles.
First-time director Trevail Maurice shows a real love for this show and it is illustrated in his highly effective seamless staging and fast-paced movement of a huge musical. His casting was impeccable. Also serving as scenic designer, his unit set with the upstage catwalk served the show wonderfully and eliminated any need for scene changes.
Ellen Licitra has outdone herself as lighting designer for the production. The show is a cascade of color from every direction imaginable with imaginative use of lighting in almost every nook and cranny. Another reason Licitra is the queen of lighting designers in the area.
Musical directors Jaron M. LeGrair and Curtis Tate handled a very difficult score with ease and helped make the singing and acting seem natural and smooth.
Choreographer Kiara Jones did outstanding work with a dance intense show.
And the ostumes by Therese Pitzulo and Wendy Akers are stunning and compliment the overall kaleidoscopic effect.
Sept. 13, 14 at 7:30 pm
Sept. 8, 15 at 2:30 pm
Tickets: 330 788 8739
Editor’s Note: The Business Journal is expanding our coverage of arts, culture and entertainment in the region. Guy D’Astasfo, former entertainment editor for The Vindicator, is our new entertainment editor. Look for his stories and insights as well as future community theater reviews by J.E. Ballantyne Jr.
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Civil - Structural, Civil Engineering
Vision: Seattle is a thriving and equitable community powered by dependable transportation.
Mission: To deliver a transportation system that provides safe and affordable access to places and opportunities.
The Seattle Department of Transportation (SDOT) is a nationally recognized municipal transportation agency at the leading edge of multi-modal transportation. In our quickly growing city, accessibility, safety, affordability, and reliability – are top of mind for us every day! Our core values drive our work toward creating an equitable, sustainable, and vibrant city for all. SDOT's core responsibilities include maintenance and operations of the city's transportation right-of-way, the expansion of the city's bicycle and pedestrian network, care of over 240 bridges, permitting use of public spaces and enhancing access to the regional transit system. With approximately 950 dedicated staff, SDOT maintains an operational presence 24 hours a day, 7 days a week, in all weather conditions to serve and ensure Seattle's public mobility.
SDOT has a great opportunity for a Senior Bridge Inspection Engineer (under the City's classification specification of Senior Civil Engineer). The Roadway Structures Division primary mission is to keep the traveling public safe in the Right-of-Way (ROW) as it relates to vertical structures. Our team is a dynamic and actionable group of fully integrated structural inspection engineers, bridge operators, and bridge maintenance skilled trades for mechanical, electrical, concrete and carpentry work.
The primary duties of this Senior Bridge Inspection Engineer will be to inspect roadway structures such as bridges, retaining walls, stairways, and areaways. Bridge inspection includes routine, fracture critical and special inspections in compliance with the National Bridge Inspection Standards. Duties also include design and preparation of work orders to repair deficiencies noted during inspection, communicate these designs to work crews and conduct repair project site visits during construction, review of Capital Improvement Project (CIP) plans and permit plans, write, negotiate and mange consultant contracts for structural repair design and inspection. Prepare letters, memos and reports related to bridge operation and maintenance projects. Position also includes the responsibility of management of the bridge load rating program. Project management duties for major structural maintenance and rehabilitation work will also be assigned as needed.
Keep accurate field inspection notes and log them in Bridge Works (WSDOT bridge inspection database program).
Design repairs and prepare bridge repair work orders. Review CIP and permit plans.
Conduct meetings and communicate verbally and in writing with fellow employees, field crews, customers, and consultants.
Coordinate work with all stake holders on small and large projects.
Work at heights, in fast traffic areas, and in confined spaces.
Support and maintain environmental sustainability and best management practices.
Work as a good teammate and high individual contributor with good customer service.
Conducts meetings.
Communicates verbally and in writing with fellow employees, field crews, customers and consultants.
Go on bridge components for inspection purposes.
Support department goals in promoting diversity and social justice.
2/4/2020 4:00 PM Pacific
Requires five (5) years professional Civil Engineering experience and a Bachelor Degree in Civil Engineering or Civil Engineering Technology; (or a combinations of education and/or training and/or experience, which provides an equivalent background required to perform the work of the class).
Registration as a Professional Engineer in the State of Washington or ability to obtain it through comity before start date.
Current Washington State driver's license or evidence of equivalent mobility.
Additional Desired Qualifications:
Experience inspecting, evaluating, and rating of roadway structures, knowledge of Federal High Way Administration (FHWA) requirements relating to the National Bridge Inspection Standards (NBIS).
Experience evaluating condition of steel structures by performing non-destructive means using ultrasonic, magnetic particle and dye penetrant tests.
Experience with inspection of Moveable bridges or similar systems that are operated by electromechanical or hydraulic systems.
Proficient in Microsoft Office and computer aided drafting.
Ability to work independently and collaboratively on a team.
Ability to handle multiple tasks in a fast-paced environment with shifting priorities easily, accurately, and positively.
Detail oriented; strong organizational, time management, and customer service skills.
Able to apply maximum confidentiality in exposure to sensitive and confidential employee information.
Effectively work in a multi-cultural workplace with a diverse customer base.
About City of Seattle, Department of Transportation
Bridge Maintenance Engineering & Operations Manager
Structural Engineer Graduate or EIT (Waterfront) Virginia Beach, Virginia
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Senior Civil Engineer – County of Sonoma Santa Rosa, California
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News releases and statements
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Fiftieth anniversary of the liberation of Auschwitz concentration camp
2/4/2018 , News releases and statements / The Holocaust and the ICRC
Auschwitz concentration camp. Lookout tower. Photo: SOMMER, Karen Margrethe/ICRC.
First published on the 28th of February 1995, The International Review of the Red Cross, No. 304
The fiftieth anniversary of the liberation of Auschwitz concentration camp was held on 26-27 January 1995. In addition to many survivors and distinguished guests, the ICRC attended in its capacity as Nobel Peace Prize laureate.
Attending the ceremonies at Krakow and Auschwitz were several hundred survivors of the camp, representatives of associations of former deportees, 19 heads of State and numerous distinguished guests, including Mr Elie Wiesel and Mrs Simone Veil.
Invited in its capacity as Nobel Peace Prize laureate, the ICRC was represented at these ceremonies by its President, Mr Cornelio Sommaruga; Mrs Liselotte Kraus-Gurny, a member of the Committee; Mr Charles Biedermann, Director of the International Tracing Service; Mr François Bugnion, Deputy Director for Principles, Law and Relations with the Movement, and Ms Ewa Tuszynski, interpreter.
Commemorating the liberation of Auschwitz
The holocaust and the ICRC
Remembering the Shoah: The ICRC and the international community’s efforts in responding to genocide
Tags: Auschwitz, Cornelio Sommaruga, Holocaust, Shoah
The ICRC started work in Israel and the occupied territories in 1948, following the first Israeli-Arab conflict. Its presence became permanent in the aftermath of the 1967 war. The organization focuses on the protection of civilians and the welfare of detainees held in Israeli and Palestinian places of detention, and helps the most vulnerable. The ICRC supports the Palestine Red Crescent Society and the Magen David Adom (the Israeli National Society).
מעבר לבלוג בעברית
Twitter @ICRC_ilot
Syria Pledging Conference: ICRC President’s call to the international community
Hunger strikes in prisons in Israel and the occupied territories
Responding and giving medical treatment during an Earthquake: dozens of youths participated in MDA unique training, which included working methods of the Red Cross Movement
ICRC in depth
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Panorama: ICRC in Action Worldwide
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BW Media Spotlight
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SNS> Kamen Rider Dragon Knight episode 1
I finally had the opportunity to finish watching this one. Adapted Power Rangers-style from a Japanese series, Kamen Rider Dragon Knight succeeds where Saban’s Masked Rider failed, by faithfully adapting the concept, while reworking it with English actors and stories.
Additionally, the show has great special effects for a kids show (and some adult sci-fi shows) which even won it an Emmy, great fight scenes, and an epic storyline. So why haven’t they put this out on DVD yet?
Kamen Rider Dragon Knight episode 1, posted with vodpod
The “Kamen Rider” series is big in Japan. Based on a concept by Shotaro Ishinomori, Kamen Riders are people with the ability to transforms into superheroes. The original Kamen Rider design was based around insects, although current versions of the “Heisei“era of the series bear only a passing resemblance to their “ancestors” of the “Showa” era. Much like Godzilla, the designations refer to a point where the franchise ended for a period only to be rebooted later. I’ve never looked up the individual terms until now.
The original version of this show, Kamen Rider Ryuki, followed a similar story, but there are differences. In Ryuki, a bumbling journalist is drawn into something closer to the Highlander franchise, where the Riders battle each other and the winner getting a wish fulfilled. Not knowing this, but knowing that monsters were kidnapping people, Shinji Kido makes a contract with the dragon much like Kit did (although this particular dragon isn’t quite as friendly as Kit’s “Advent Beast”). You’ll see in the next episode (if you check out the series) how Kit ends up becoming Dragon Knight, but his is purely a battle of protecting the worlds of Earth and Ventara from an evil force.
Sadly, Victoria Jackson doesn’t appear after the earlier episodes. The other actors on the show, including the ones that come after, do a great job in their roles. Sometimes the effects are obvious but not a distraction if your caught up in the stories and battles. They must have done something right. Kamen Rider Dragon Knight even aired in Japan, where Ryuki apparently didn’t fare too well. (Based a passing comment on the Series Wikipedia page, so who knows. TV Tropes claims that the US version was a hit.) The show even received the first Daytime Emmy Award for Stunt Coordination.
So why is there no domestic release for the DVD? Wiki blames it on the series being canceled, with the last three episodes (a two-parter and epilogue) hosted at 4KidsTV.com. Where ratings bad? TV Tropes seemed to think so, but I can’t find the actual ratings. I would love to have this series on DVD. The only Kamen Rider show we get is a remake of the original. We’re really missing out on a great franchise, including one series that the US did right. At least for now, you can watch the on 4Kids’ website (at least domestically) and you really should.
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Posted by ShadowWing Tronix on September 25, 2010 in Saturday Night Showcase, Television Spotlight and tagged Kamen Rider Dragon Knight, Kamen Rider Ryuki.
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