text:
“It is a means for the fresh university to display their dedication to supporting LGBTQIA+ neighborhood people and also for the partnership to possess suggesting to own security to have LGBTQIA+ college students, faculty and you will staff,” Lemke told you.
Lemke prompts individuals explore satisfaction festivals going on in other aspects of Utah as well for the rest of Summer.
“Therefore really, what pride mode, differs LGBTQIA+ communities making this celebration this observation regarding man’s activism and you can people’s refusal is silenced or even end up being invisible, very honoring the new organizations that they are in through the regional festivals and you will just what it works out so they are able enjoy pleasure from inside the their rooms,” Lemke said.
Queer Liberation and you will Leading edge Soul
“Over the years, nonprofits that have adopted new Gay and lesbian battle, have inked very in many ways which were very capitalistic and you can full of corporate-based avarice, in place of the radical root,” she said.
Fanaeian could be speaking at Salt Lake People Shared Aid’s Pride As opposed to Cops experience towards June 10 – it event supporters to possess queer liberation unlike consumption while the leading edge soul characterizing pleasure actions historically.
“Unlike the rainbow capitalists just who positively receive cops to the queer spaces, we sit with great revolutionaries such as for instance Marsha P , Sylvia Rivera , and Harry Hay for the acknowledging that the police condition have constantly started and certainly will continually be an opponent of your own queer liberation course,” the brand new group’s Instagram post understand.
“We have picked to incorporate the authorities in this event but i also empathize with individuals who have a problem with you to definitely, while the in past times, police provides hurt our very own community, so we keep in mind that,” the guy said. “However, we, currently, have a good reference to law enforcement department, and wish to manage you to, we would like to provides an almost all-inclusive event for everybody, hence includes the police.”
Predicated on Fanaeian, this new Pride Versus Cops enjoy is important to help you “award the true anti-capitalist, anti-cops, revolutionary, revolutionary sources of your queer and you can trans battle.”
Armed Queers are good socialist category assaulting to own public security off the fresh new queer area. Which, Fanaeian told you, becomes necessary, as the police don’t include him or her.
“I will be these are the need for queer and trans https://datingmentor.org/senior-sizzle-review/ people to case ourselves from the second off hostility as well as the time of governmental tensions expanding against us and really put off [to] public defense and communal safeguards of just one several other,” she said.
“It’s a time for you most develop you to throwing with techniques you to we aren’t in a position to grow during the maybe other times of your own year,” she told you. “It’s about increasing the latest battle and growing our moves.”
The original satisfaction parade occurred from inside the 1970, 12 months after the Stonewall Riots, in which individuals protested police raids of Stonewall Inn, a pub and set out-of refuge for new York’s gay people
Case will get speeches of queer organizers, 100 % free dinner, musical and you may moving. Independent queer performers is head message brand new SLCMA’s Instagram in order to dining table at the skills.
Fanaeian told you pleasure is not for firms, thus as an alternative they should read the way they features led to this new need for pride festivals to start with.
“[Corporations] need to accommodate its queer and you can trans workers to help you unionize and manage to stand up up against a few of the oppressive ways in which it clean out him or her,” she told you. “In my opinion they have to understand that they are reason trailing far oppression and you may exploitation up against us.”
The newest College or university off Utah will receive a walking delegation on the Satisfaction Procession , supported by this new Lgbt Resource Target university, one of most other collaborators.


I’m back on BBC Radio Scotland’s Breaking the News today (Friday 16 March) at 1.30pm and again on Saturday at 11.30am. It’s a busy one, covering everything from the Cold War, to quantum mechanics, pandas, pigs and spitting!
It’ll be available as a podcast or on the iPlayer soon after the first show.
There is only one week to go until my new show Salad Spinner at Glasgow International Comedy Festival. There are 3,628,800 versions of the show, anything could happen! Well, one of 3,628,800 things will happen.


text:
I’m not really good at flirting; at least, when I’m trying to flirt. I don’t get how people *cough* Josh *cough* can naturally do it so fucking well. Every time I try I just end up feeling hopelessly awkward. So then I close up and get in my head. How the hell do you practice flirting so you don’t make a fool out of yourself? I think I only feel awkward because the girl doesn’t flirt back… because I’ve been friend-zoned… how do I get the girl to flirt back? …I look like I’m 12. I want to look older. Maybe that’s why. I look (and act) more like a younger brother to girls. That would explain the lack of romantic interest the female population has for me. I’m just weird… and awkward… and an idiot. Sometimes I get the feeling that people don’t actually want to be around me but they’re too nice to say so. Okay not sometimes, all the time. I kind of just show up and awkwardly follow people around. Then I just stand silently in conversations because I’m not exactly that interesting. So I look and feel out of place. Then I try to say something and no one really listens to me… so I just stay silent the rest of the time because my thoughts were confirmed: no one actually cares …great. I’m not really assertive. I need to change that. Stupid. I’m constantly afraid of losing these new friends I have made. At least, I’m pretty sure we’re friends… it’s not like many people really go out of their way to hang out with me… I hate my life. I’m just lonely, all the fucking time. It’s great when I end up hanging out with people, but they can’t hang out all the time; I shouldn’t expect that of them. I want to be the center of someone’s attention. Just one person… is that too much to ask? I’m going to be so depressed during spring break. Everyone is probably leaving. I haven’t been invited to do anything, because no one seems to want me around right now… or ever. So I’m going to be stuck at home… hating everything. I’m praying for that outcome to change. But it probably won’t. Why? Because life sucks, that’s why.
And now a funny picture, to cancel out the negative:

domain: sociology


O'BYRNE CUP ROUND-UP: Kildare made sure of their passage to the O'Byrne Cup semi-final last night in Newbridge when they beat DIT by 0-12 to 0-8.
In a match which at one point, seemed certain to fall foul of the heavy fog, Mikey Conway impressed hugely for the second game in four days from centre-back, kicking three points (two frees) and in truth, the Lilies were even more dominant than the final scoreline suggests.
They led by 0-9 to 0-5 at half-time and Kieran McGeeney will have noted the strong displays from newcomers Cathal McNally (0-2) and Daniel Flynn (0-1). His team were, however, reduced to 14 men in the 49th minute when Gary White was dismissed for a second yellow card but then proceeded to kick the next three points of the match.
DIT, featuring last year's Dublin under-21 captain Kevin O'Brien as well as fellow panelists Seán George, Paul Maguire and Ciarán Reddin, dominated the last 15 minutes or so with Mayo's Aidan O'Shea and Cork's Mark Collins particularly prominant, although they couldn't close the gap sufficiently to make life any more difficult for Kildare.
In the night's other Group D match, WEXFORD slumped to a second successive competitive defeat after they fell to CARLOW IT in Bunclody last night by 0-12 to 0-10, with Ben Brosnan doing plenty of the damage by kicking three points from play against his own county.
In Group C, OFFALY took a giant step towards the last four of the competition and eased to both points with a 3-11 to 1-9 win over ATHLONE IT in Gracefield.
The match was actually level in the 41st minute but second-half goals from Peter Cunningham, Brian Connor and Eoin Carroll - added to Niall McNamee's impressive haul of 0-6 (3f) - meant the home side cruised to a second successive victory of 2013.
In the only Group A match of the night, LONGFORD pipped an understrength UCD by a goal - 1-14 to 0-14 - after dominating the opening exchanges.
Glenn Ryan's men led by 0-7 to 0-0 after 16 minutes and Aidan Rowan's late first-half goal meant the second half was largely academic.
CARLOW, meanwhile, survived the loss of two players to red cards in Bray last night to beat WICKLOW by 0-12 to 0-9 in Group B. Anthony Rainbow's men led by 0-7 to 0-6 at the break and withstood the absence of Darragh Foley and Shane Mernagh for a large chunk of the second half after both were shown the line.
p MEATH'S Group A clash with Louth was postponed due to heavy fog in Navan. The match has been refixed for tonight at 7.30 in Páirc Tailteann.


text:
The sparse nature of voluntarily reported drug safety data benefits from a system that consolidates the massive amount of data into a manageable format for analysis. This has been done for Australian drug safety data by the Australian Adverse Drug Reaction Advisory Committee (ADRAC) for reactions using the systems organ class (SOC) ontology. There has long been a need for a similar kind of grouping to apply to drugs in this type of data. In ADRAC, drugs are currently listed by trade-name, where only some of these trade-names were assigned anatomical-therapeutic-chemical classification (ATC) codes. We assigned an ATC code for each ADRAC trade-name and show that this ontology facilitates the detection of drug class / reaction class associations at various levels of specificity. This allows different views of these associations (even very rare ones) and their significance measured for the development of more sensitive signal detection methods. We report that this ATC classification enables both the grouping of association rule approach that is useful for studying rare associations, and the development of an adverse reaction signal detection method.
Adverse drug reactions (ADRs) are estimated to be one of the leading causes of death. Many national and international agencies have set up databases of ADR reports for the express purpose of determining the relationship between drugs and adverse reactions that they cause. We formulate the drug-reaction relationship problem as a continuous optimization problem and utilize C-GRASP, a new continuous global optimization heuristic, to approximately determine the relationship between drugs and adverse reactions. Our approach is compared against others in the literature and is shown to find better solutions. 1.

domain: medical


text:
There is something to admire in entrepreneur students. Juggling studies and at the same time worrying about how to build a business is not a cup of tea for everyone.
But this excited Aliff, a UKM student. While studying, he launched Charming Malaysia, a milk tea and coffee drink.
The idea for the business came from a conversation Aliff had with his two friends, who were drinking Cham Peng (a combination of iced coffee and tea) at the time.
Having never heard of this drink before, he tried it and found it unique and delicious.
“So, I decided to come up with a product that allows people to taste Cham anywhere and anytime, instead of having to go to a kopitiam whenever they want,” Aliff shared.
His 3-in-1 product is born, with the “Charming” brand that represents the experience that is derived from the charm and beauty of the aroma of coffee and tea combined.
Charm his friends and family with Cham
Once the idea materialized, Aliff then decided to research the general taste of Cham and eventually came up with his own version of Cham. Then came the validation phase of his he product, for which he turned to relatives and friends.
“Most of the comments were positive, and that’s when I realized I should be distributing this drink to others,” Aliff said.
As Charming is relatively new to the market, Aliff believes patience is essential to create demand.
Currently, Charming’s official website rates its 12 sachets of Cham at RM 20.99. While some may argue that this may be above the average price of 3-in-1 drinks, Aliff has its reasons.
“After conducting a market investigation, we found that our prices are still comparable to those of other brands that sell Cham,” justified Aliff.
Furthermore, the founder said that Charming includes two varieties of coffee beans, Robusta and Arabica, and three varieties of tea, black, red and green. With such a blend, consumers get more complexity and depth in flavor.
In further justifying the price of the product, Aliff said he took production costs into account when determining the prices.
Focusing on marketing now
In terms of production, Charming collaborates with a factory owner to produce its 3-in-1 Cham sachets.
This allows the team to focus on spreading and promoting the brand in the best possible way. For example, for their first anniversary in business, the team organized a giveaway.
214 attendees took part in this giveaway, and as a result, the beverage brand gained more than 200 new followers.
Aliff said this marketing strategy proved their methods were viable and effective. She also plans to use other advertising methods such as influencer marketing, sponsoring sporting events, and running free sample events.
“With the factory managing the entire production of Charming, I think the hard part would be finances,” shared Aliff.
Along the way, the brand faced some difficulties in finding investments. However, Aliff was positive enough that he would overcome this, stating that this was a common challenge for every entrepreneur.
Looking at the big picture
According to Aliff, there are only a few beverage brands that have introduced Cham to the Malaysian market, but they are hardly found in grocery stores.
“Therefore, fascinating plans to lead the Malaysian market to embrace the Cham flavor as there are still so many who are not familiar with the taste,” said Aliff.
Moving forward, Charming plans to introduce a new product, Kopi-O, which will give consumers a taste of “kampung”.
Along with this, Charming will also release a number of coffee flavors including cappuccino, mocha and latte.
Explaining his future plans further, Aliff says he has a five-year plan that will guide him in the expansion of Charming.
Within three years, he intends for the first time Charming to make its way into well-known grocery stores such as AEON Big and Lotus.
If this is accomplished, then he would like Charming to be stocked in as many Malaysian grocery stores as possible in the following years.
- Find out more about Fascinating here.
- Read other Malaysian startups here.
Featured Image Credit: Fascinating

domain: news


text:
Getting good quality sleep, can be a little difficult during the winter. This is because winter brings humid, dry areas which can affect our sleep quality. Dry air causes dry irritated eyes, sore throat, chapped skin and lips, sore throat, dry nasal passage as well as cold or flu.
One great way to combat this is by getting a humidifier. This can help you keep their air from becoming too dry when you fall asleep. With a humidifier, controlling the room’s humidity will be easier. You can keep it at an optimal level to reduce these issues and promote a good night’s sleep
How do humidifiers work?
Humidifiers are machines designed to force extra moisture into the air, thus increasing the humidity. There are two types of humidifiers, the warm mist/steam humidifier, and the cool air/cool mist humidifier.
Warm steam humidifiers work by creating warm moisture from water/boiling water to release some warm air/steam into the air. These are perfect for the winter season. Cool mist humidifiers on the other hand incorporate water into the cold air to produce cool, moist air. There are also ultrasonic, high-frequency cool air humidifiers that have a diaphragm that vibrates at high ultrasonic frequencies to convert water into tiny air droplets, creating humidity in the air.
Benefits of using humidifiers
Helps prevent colds and flues
Humidifiers help Alleviates cold and flu symptoms and may come in handy in preventing influenza. By using humidifiers while you sleep, you create favorable humidity levels and breathing conditions, which in turn alleviates cold symptoms and helps prevents any infections.
If you suffer from sinuses, especially during the cold months you can use humidifiers to keep the air moist and prevent your nasal passage from drying out. In the long run, this can prevent sinusitis or aggravated allergies.
May help reduce snoring
Dry air is a popular cause of snoring. This is because it causes your nasal cavity to dry out. This causes dry air to be trapped inside your airways leading to vibrations when you breathe in and out as you sleep. The vibrations and difficulty breathing are what produce the snoring sounds.
A dry nasal cavity can also cause a buildup of thick muscles which intensifies the snoring. Getting a humidifier is one way to get rid of this problem. Humidifiers add some moisture into the air, which means the air is not as dry and your nasal cavity and throat will not dry out as you breathe. The moisture in the air allows it to move freely as you breathe, reducing the level of difficulty in breathing and therefore less snoring.
Do they have any drawbacks?
While humidifiers have their benefits, they also have some disadvantages. One of the biggest and most common issues about having a humidifier is its maintenance. If water is left in the machine for long periods of time, it could grow mold or bacteria, which can lead to serious health concerns. Regardless of the brand, you need to clean your humidifier regularly to reduce the risk of serious infections.
When is the best time to get a humidifier?
During the winter season, people generally spend their time indoors in well-heated rooms. This can make the air in the house a bit dryer. Dry air causes sore throats, cold and difficult breathing, especially during sleep. If you suffer from these, you can buy essential oils from Revive that can greatly help for your relief. Because of this, many people may need to use a humidifier to introduce moisture into the air during the winter season.
During the summer
Air can also be unnaturally dry during the summer. Air conditioning tends to remove moisture from the air, leaving it dry and this may cause some serious health issues. Dry sinuses, dry throat, dry nasal passages, and inflammation are very common during the summer. Using a humidifier during this period may help alleviate these symptoms and help you sleep better during the night.
While it is a small change, humidifiers can go along way into giving you better, healthier sleep. However, you need more than just a humidifier to get a good night’s rest. Together with a high-quality mattress like the ones from Sleep Number, Quality sheets, blackout curtains and a comfortable bed, you can achieve high quality and quantity of sleep. Add plants to your bedroom that purify the air, and the international florists at MyGlobalFlowers can advise you on which plants to use. With these combinations, you can be sure to get the best sleep and a quality, productive time during the day.


The Why Store is the best band ever to come out of Indiana. Listening to their music reminds me of home (Indiana) and always makes my ears happy. Buy any CD by. The Why Store is 'officially open for business'. Led by Chris Shaffer an intense, emotional songwriter with a repertoire of + original songs and 30+. In , the band independently recorded Welcome to the Why Store. One year later the band recorded Inside the Why Store. Both albums were huge regional. Discover releases, reviews, credits, songs, and more about The Why Store - Welcome To The Why Store at Discogs. Complete your The Why Store collection. The Why Store Profile: A folk and blues driven rock, originally formed in at Ball State University in Muncie, Indiana by Michael David Smith, Greg. Find album reviews, songs, credits and award information for Welcome to the Why Store by The Why Store on AllMusic - That same year, the band switched to its present name, The Why Store, the name of a former Muncie , the band independently recorded Welcome. Biography. The Why Store began in , when Chris Shaffer, Greg Gardner, and Michael David Smith met as students at Ball State University in Muncie. Find top songs and albums by The Why Store including Lack of Water, In , the band recorded Welcome to the Why Store for Blee-Hee-Hee Records and. Shop Welcome to the Why Store [CD] at Best Buy. Find low everyday prices and buy online for delivery or in-store pick-up. Price Match Guarantee.


text:
Fortnite AFL Tournament (Jan) Know Details To Win! -> The FORTNITE game has launched a charity football match. You can also participate and win cash rewards after reading our post.
Are you searching for “Fortnite AFL Tournament” details? Many FORTNITE gamers are asking us to illustrated information on the game charity tournament. We will also depict how you can win the rewards by playing smart. However, it would be best to peruse our article until the end to know more about it.
The FORTNITE tournament is gaining popularity in the United States and Australia. It is because the gamers from these two countries are fighting against each other to win big rewards. Are you ready to win the prizes? Please continue reading the post!
What is Fortnite AFL Tournament?
The FORTNITE game is launching a football Tournament that will be played by Australian and United States gamers. Besides, the winning amount is set 100000 AUD dollars. You can grab the winning amount by participating in the tournament and beating the competitors. FORTNITE gaming platform is famous for launching cash-rewarding tournaments, matches, battles, and other duo-game events.
When will the tournament begin?
It is suggested that the tournament will begin on 21st MAY 2021 and end on 22nd MAY 2021. Since the stakes and winning amount is high, the AFL expects record-breaking player registration as the action unfolds. The tournament will enlist 40 Australian players who will battle to score ranks for 50000 AUD dollars.
The “Fortnite AFL Tournament” will credit the winning amount into your account as soon as you win. Are you confused as how many players can win? We are listing the winning pool in the upcoming section.
How many players can win?
As mentioned earlier, the Australian league players can win up to 50000 AUD dollars. However, the winning amount will be divided into three winners. The amount of segregation is listed below:
- The first winner will be awarded 50000 AUD Dollars.
- A player securing the second position will get 30000 AUD Dollars.
- The third winner will get 15000 AUD dollars.
- There is one place for a winner to get 5000 AUD Dollars. It will be credited into the gamer’s account, which will score the fourth position.
As 2020 has tested everybody worldwide on different parameters, the Fortnite AFL Tournament will give the players an equal winning opportunity. The FORTNITE developers are using the tournament for a charity event to help other people who are not gamers. Therefore, many studios and organizations are joining hands for this noble and exciting cause.
Our Final Thoughts:
ROCKSTAR GAMES AND KOJIMA PRODUCTIONS have joined hands with FORTNITE to launch the tournament in May 2021. The players get three months to practice and increase the chances of their winning. Similarly, you can practice by competing with the top FORTNITE gamers and learn the tricks to win. The Fortnite AFL Tournament is not far away if you wish to win 5000 to 50000 dollars by playing games. Kindly share your views on this significant charity event!

domain: hobby


text:
Redwall : Redwall Series, Book 1. / Brian Jacques.
View other formats and editions
- ISBN: 9781101665985 (electronic bk)
- Physical Description: 1 online resource.
- Publisher: [Place of publication not identified] : [publisher not identified], 2002.
The question in this first volume is resoundingly clear: What can the peace-loving mice of Redwall Abbey do to defend themselves against Cluny the Scourge and his battle-seasoned army of rats? If only they had the sword of Martin the Warrior, they might have a chance. But the legendary weapon has long been forgotten-except, that is, by the bumbling young apprentice Matthias, who becomes the unlikeliest of heroes. Teeming with riddles, humor, unforgettable characters, and high-bounding adventure, the original Redwall, the launching point for a series that has captured the world's attention, features seven full-color illustrations by renowned illustrator Troy Howell. This new paperback edition is a must-have for both longtime fans and first-time readers.
Electronic reproduction. New York : Firebird, 2002. Requires OverDrive Read (file size: N/A KB) or Adobe Digital Editions (file size: 5337 KB) or Kobo app or compatible Kobo device (file size: N/A KB) or Amazon Kindle (file size: N/A KB).
Search for related items by subject
Search for related items by series

domain: literature


text:
made in britain
can be personalised
A beautiful oak and walnut wood christening keepsake
A wonderful momento for their wonderful day, beautifully engraved into the oak block will be words 'On your christening day', date and place of christenin, godparents names and a personal message.
Baby's name will be inlayed with exquisite walnut wood, beautifully presented to keep forever.
The solid oak and walnut wood keepsake is a truly beautiful and a lovely way to remember the little ones christening.
It really is a beautiful keepsake.
Stands beautifully proud on a shelf or mantlepiece or can be hung on a wall, it is stunning.
Makes a wonderful momento and something that can be kept forever.
Each Oak and walnut wood block is personalsed for you.
Solid oak and walnut wood
32 cm x 17 cm x 5 cm

domain: design


text:
Cancer in adolescents and young adults (AYAs) (15–39 years) is increasingly recognized as a distinct clinical and biological entity. Cancer of unknown primary (CUP), a disease traditionally presenting in older adults with a median age of 65 years, poses several challenges when diagnosed in AYA patients. This study describes clinicopathological features, outcomes and challenges in caring for AYA-CUP patients.
A retrospective review of 47 AYAs diagnosed with CUP at MD Anderson Cancer Center (6/2006–6/2013) was performed. Patients with favorable CUP subsets treated as per site-specific recommendations were excluded. Demographics, imaging, pathology and treatment data was collected using a prospectively maintained CUP database. Kaplan-Meier product limit method and log-rank test were used to estimate and compare overall survival. The cox-proportional model was used for multivariate analyses.
Median age was 35 years (range 19–39). All patients underwent comprehensive workup. Adenocarcinoma was the predominant histology (70%). A median of 9 immunostains (range 2–29) were performed. The most common putative primary was biliary tract based on clinicopathological parameters as well as gene profiling. Patients presented with a median of 2 metastatic sites [lymph node (60%), lung (47%), liver (38%) and bone (34%)]. Most commonly used systemic chemotherapies included gemcitabine, fluorouracil, taxanes and platinum agents. Median overall survival for the entire cohort was 10.0 (95% confidence interval (CI): 6.7–15.4) months. On multivariate analyses, elevated lactate dehydrogenase (Hazard ratio (HR) 3.66; 95%CI 1.52–8.82; P = 0.004), ≥3 metastatic sites (HR 5.34; 95%CI 1.19–23.9; P = 0.029), and tissue of origin not tested (HR 3.4; 95%CI 1.44–8.06; P = 0.005) were associated with poor overall survival. Culine’s CUP prognostic model (lactate dehydrogenase, performance status, liver metastases) was validated in this cohort (median overall survival: good-risk 25.2 months vs. poor-risk 6.1 months).
Citation: Raghav K, Mhadgut H, McQuade JL, Lei X, Ross A, Matamoros A, et al. (2016) Cancer of Unknown Primary in Adolescents and Young Adults: Clinicopathological Features, Prognostic Factors and Survival Outcomes. PLoS ONE 11(5): e0154985. https://doi.org/10.1371/journal.pone.0154985
Editor: Andreas Krieg, Heinrich-Heine-University and University Hospital Duesseldorf, GERMANY
Received: November 2, 2015; Accepted: April 23, 2016; Published: May 12, 2016
Copyright: © 2016 Raghav et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Both legal and HIPAA restrictions do not allow us to publicly upload the data. Any data availability requires data utilization agreement. Furthermore, in this small dataset several cells have fewer than 10 patients and therefore HIPAA restrictions limit disclosure of data. However, data are available from the MD Anderson Institutional Cancer of Unknown Primary Database on request for researchers who meet the criteria for access to confidential data. Requests for data access may be sent to either the corresponding author or to The University of Texas MD Anderson Cancer Center's Office of Research Administration (eRSCH@mdanderson.org).
Funding: This work was supported by the Painter Research Fund.
Competing interests: The authors have declared that no competing interests exist.
Cancer in adolescents and young adults (AYAs) (15–39 years) is increasingly recognized as a distinct clinical and biological entity [1, 2]. AYAs with cancers have historically received less attention than either children or older adults with cancers. Managing cancer in these patients comes with several challenges owing to their unique clinical, psychological and socioeconomic demands [1–3]. Additionally, participation of AYAs in clinical trials has been inadequate for many reasons resulting in a relative lack of progress in this vulnerable group of cancer patients [4, 5]. Initiatives to overcome these impediments and research dedicated to cancers in AYAs have been encouraged by the National Cancer Institute to improve our understanding of cancers in this age-group and patient outcomes .
Cancer of unknown primary (CUP) is a heterogeneous group of cancers, for which despite detailed evaluation, the anatomical site of origin remains obscure [7, 8]. This is typically, a disease of older individuals, with a median age of 67 years. Management of these cancers requires a thorough physical examination, focused imaging and pathologic review. Treatment is site-specific therapy based on a putative primary when informed; otherwise, empiric platinum based chemotherapy is employed . Nevertheless, survival outcomes in CUP patients remain suboptimal with a 9–13 month median overall survival in good performance status patients in empiric phase 2 studies .
A diagnosis of CUP in an AYA patient, although a rare clinical scenario, can present a formidable encounter. The trauma associated with a rare cancer entity coupled with the uncertainty regarding prognosis causes anxiety, leads to second guessing of the diagnosis, makes patients to feel isolated from other cancer patients with known primary cancers, and adversely affects the quality of life and treatment of these patients. Prior studies have demonstrated that AYAs have worse survival compared to their older counterparts in a variety of cancers, including colon and breast cancer; however the outcomes of AYAs with CUP has not been reported [1, 10]. Therefore, we performed this retrospective analysis of AYAs with CUP with the purpose of describing the clinicopathological profile and survival outcomes of CUP in AYAs, and delineating prognostic factors.
Materials and Methods
We retrospectively reviewed data from 47 AYA patients who were evaluated and treated for CUP at The University of Texas M.D. Anderson Cancer Center, Houston, TX over a period of 7 years, between June 2006 and June 2013. The study was performed under a protocol approved by the institutional review board at M.D. Anderson Cancer Center and a waiver for informed consent was obtained. Patient records/information was anonymized and de-identified prior to analysis. For the purpose of this study, per ASCO guidelines, AYAs were defined as individuals between the ages of 15 and 39 years . CUP was defined as presence of biopsy proven metastatic cancer without a detectable primary after a focused and comprehensive work-up including history and physical, laboratory assessment, pathology review including immunohistochemistry and diagnostic imaging with computerized tomography of chest, abdomen and pelvis . Data on clinical presentation, demographics, imaging, pathology and treatment was collected from a prospectively maintained CUP database and the electronic medical record. Vital status was confirmed using tumor registry and patient records. Two clinicians independently reviewed each case and assigned a putative primary site based on the available clinicopathologic data. In cases where one of the physicians was involved with the care of the patient, the putative primary site was obtained from prior records and the second physician was blinded to this variable.
Patient and tumor characteristics including age, gender, ECOG performance status, number of metastatic sites (1, 2, 3+), site of metastases [lung, liver, bone, or lymph nodes], histology, laboratory parameters [lactic acid dehydrogenase (LDH) (≤ 618 IU/L, > 618 IU/L), albumin (≤ 4, > 4), circulating neutrophil-lymphocyte ratio (NLR) (< 5, ≥ 5)], immunohistochemistry [CK7, CK20, CDX2 (positive, negative or not performed)], first-line treatment, and use of molecular profiling tests to determine tissue of origin (ToO) were summarized using frequencies and percentages. Kaplan-Meier product limit method was used to estimate one-year overall survival and 95% confidence intervals (CI) and groups were compared using the log-rank test. Overall survival (OS) was measured from the date of diagnosis to the date of death or last follow-up for patients who were alive. Multivariate Cox proportional hazards models identified the factors predicting survival. Results were expressed in hazard ratios (HR) and 95% CI.
Methods on concordance of primary site
We checked the agreement and disagreement of the provisional primary diagnoses submitted by each of the two clinicians and the putative primary stated by the ToO test. Cohen’s Kappa coefficient with 95% CI was used to assess the degree of agreement between two clinicians and ToO result. McNemar’s test was used to test the marginal homogeneity of the two clinicians agreeing with the results based on the ToO test; that is, whether they have the same tendency to agree or disagree with the results of ToO.
All tests were two-sided and P-values less than 0.05 were considered statistically significant. Statistical analyses were carried out using SAS 9.3 (SAS Institute Inc., Cary, NC), S-Plus 8.2 (TIBCO Software Inc.).
Of the 714 CUP patients, 47 (6.5%) AYAs with CUP were included in the analyses. The baseline characteristics and key clinicopathologic features of this cohort are summarized in Table 1. The median age of diagnosis was 35 years (range: 19–39 years). Adenocarcinoma was the predominant histology (70%). Patients presented with a median of 2 metastatic sites, most common being lymph node (60%) followed by lung (47%), liver (38%) and bone (34%). Imaging including CT chest, abdomen and pelvis such as PET/CT scan, upper endoscopy, colonoscopy and mammography were performed in 60%, 51%, 47% and 40% patients, respectively. Most patients received systemic chemotherapy using gemcitabine, fluorouracil, taxanes and platinum agents, although a select few with solitary or oligometastatic disease were treated with radiation and surgery as primary modality therapy. Molecular profiling to determine the tissue of origin was performed in 26 (55.3%) patients with a positive prediction in 19 (73.0%) cases.
Univariate and multivariate survival analyses
The median follow up for the entire cohort was 8.6 months (range: 1–55 months) and at the time of the analysis, 30 (63.8%) patients had died. The 1-year OS for all patients was 47.0% (95% CI: 31.0%– 61.0%) and median OS of the entire cohort was 10.0 months (95% CI: 6.7–15.4 months) (Fig 1A).
On univariate analysis, number of metastatic sites (median OS for 1, 2, ≥3 sites: Undefined, 10.4 months, 8.4 months), presence of lung metastasis (median OS for metastasis 8.4 months vs. no metastasis 14.9 months), elevated lactate dehydrogenase (median OS for elevated LDH 6.1 months vs. normal 15.4 months), and tissue of origin tested (median OS for ToO not tested 8.6 months vs. ToO tested 15.4 months) significantly impacted OS (Fig 1C and 1D) (Table 2). On multivariate analysis, elevated lactate dehydrogenase (HR 3.66; 95%CI 1.52–8.82; P = 0.004), 3 or more metastatic sites (HR 5.34; 95%CI 1.19–23.9; P = 0.029) compared to 1 site, and tissue of origin not tested (HR 3.4; 95%CI 1.44–8.06; P = 0.005) were associated with worse survival (Table 2).
Validation of Culine prognostic model
Patients were risk stratified using the Culine prognostic model for CUP and classified as good risk (ECOG performance status of 0 or 1 and normal LDH or no evidence of liver metastases if LDH unknown) and poor risk (ECOG performance status of 2 or more or elevated LDH or presence of liver metastases if LDH unknown) . Median survival of good risk patients was 25.2 months compared to 6.1 months for poor risk patients (HR 2.53; 95% CI 1.28–5.67; P = 0.008) (Fig 1B).
Methods on concordance of primary site
Molecular tumor profiling predicted a tissue of origin in 19 of 26 (73.0%) cases; most common being biliary tract 5 (26.3%), ovarian 4 (21.0%) and gastroesophageal 2 (10.5%) primaries. The two clinicians were in agreement with regards to the putative primary in 33 of 47 cases (70.2%) and showed strong concordance (coefficient 0.89 [95% CI: 0.70–1.0]) amongst them. Of the available 19 cases where the putative primary was known based on the results from ToO test, the two clinicians individually agreed with these diagnoses in 9 (47.4%) and 10 (52.6%) cases showing fair concordance (coefficient 0.36 [95% CI 0.1–0.5] and 0.44 [95% CI 0.2–0.7]), respectively. The McNemar’s test revealed a P value of 0.37, indicating that the two clinicians had the same propensity to either agree or disagree with the results based on ToO test.
Case 1: A 17-year old previously healthy young man, without any significant family history of cancer, presented with progressive shortness of breath, cough, weight loss and back pain for past 3 months. Blood tests showed markedly elevated CA19-9 and CEA and normal Alpha feto-protein, Beta-HCG and chromogranin-A. CT imaging revealed too-numerous-to count bilateral lung metastases, mediastinal lymphadenopathy, and diffuses bony metastases (Fig 2A). Testicular ultrasound was normal. Lung biopsy revealed a poorly differentiated adenocarcinoma with immunohistochemistry (IHC) positive for CEA, CK20, CDX2, and negative for CK7, TTF-1, Napsin A, synaptophysin, and chromogranin. Upper endoscopy, colonoscopy and MR enterography done at an outside institution were negative for a primary cancer. Given the intestinal IHC profile, he was started on a colon specific regimen with 5FU and oxaliplatin (mFOLFOX6) to which bevacizumab was added after several cycles. He responded well to this regimen with clinical benefit noted in his cough and pain symptoms and decrease in CEA and CA19-9 (Fig 2D). Repeat CT imaging after 12 cycles of chemotherapy showed excellent partial response and he was on maintenance 5FU after oxaliplatin hypersensitivity (Fig 2B). On progression, patient was treated with additional colon cancer based regimens including 5FU and irinotecan with mild progression. Insufficient tissue prompted a repeat biopsy for biomarkers to help guide further lines of therapy. A next generation sequencing (NGS)-based analysis for the detection of somatic mutations in the coding sequence of a total of 50 genes was performed on the DNA extracted from the sample and showed mutations in SMAD4 and NRAS. Tumor was microsatellite stable. Cetuximab was not used and an attempt at empiric taxane based therapy and protocol-based MEK1-2 inhibitor showed no response with worsening disease (Fig 2C). He died 18 months after his initial presentation.
A) CT Chest at diagnosis shows multiple pulmonary metastases, B) CT Chest after 12 cycles of chemotherapy with 5-Fluorouracil and oxaliplatin showing radiographic response, C) CT Chest after 4 cycles of 5-Fluorouracil and irinotecan and clinical trial involving MEK1-2 inhibitor with progression of disease, D) Trend in tumor marker, carcinoembryonic antigen (CEA).
Case 2: A 24 year-old previously healthy young woman presented with a 2 month history of abdominal discomfort and bloating. Imaging revealed a 21 cm upper abdominal mass and peritoneal carcinomatosis (Fig 3A). Biopsy of the abdominal mass revealed a malignancy with epithelioid differentiation, favoring poorly differentiated adenocarcinoma with signet ring cells. Immunohistochemistry (IHC) was nonspecific and inconsistent (positive for pancytokeratin, PAX8, and CDX2, and negative for CK7, CK20, ER, WT1, calretinin, CD31, CD34, and synaptophysin) and working diagnosis was a putative upper gastrointestinal versus mullerian cancer profile. Blood tests showed elevated CA-125 and normal CEA and CA 19–9. EGD was negative and colonoscopy was incomplete secondary to extrinsic compression. Given the lack of clarity, tissue of origin testing was sent and in the interim she was started on empiric paclitaxel, 5-FU and oxaliplatin (T-FOX) for broad coverage of both upper GI and ovarian malignancies. She had progression of disease after 3 cycles (Fig 3B). At this point, tissue of origin testing results returned with a 90% likelihood of adrenocortical origin. Pathology was re-reviewed and immunohistochemical markers for adrenocortical carcinoma (ACC), including inhibin, calretinin, and melan A were negative and adrenals were normal on imaging. 50 gene mutation panel revealed no actionable mutations. She was initiated on etoposide, adriamycin and ciplatin (EAP) given activity in ACC as well as broad activity. She had response on both imaging and tumor markers after 3 cycles (Fig 3C and 3D) but unfortunately, subsequently had clinical decline and passed away approximately 6 months after her initial diagnosis. This case illustrates the discrepancy between ToO results and IHC and the challenges in managing AYA CUP patients with complex presentations.
A) CT Abdomen at diagnosis shows a large intrabdominal mass, B) CT Abdomen after 3 cycles of chemotherapy with 5-Fluorouracil paclitaxel, and oxaliplatin (T-FOX) shows progressive disease, C) CT Abdomen after 3 cycles of etoposide, adriamycin and ciplatin (EAP) shows radiographic response D) Trend in tumor marker, CA-125.
This AYA-CUP study brings to attention a few important conclusions. First, in this cohort of 47 AYA –CUP patients, median survival was about 10.0 months with 53% of patients dying within the first year of diagnosis. This is similar to unselected older CUP patients where the median survival ranges from 7–12 month [11–13]. Second, traditional prognostic factors in CUP, such as the number of metastatic sites and elevated lactate dehydrogenase levels were independently associated with poor survival which validates the Culine prognostic model in AYA-CUP . Notably, most patients seen at our institution had an evaluation done at outside institutions and it ranged widely from a minimalistic approach to excessive . The immunophenotypic markers used to characterize these tumors was also varied. Despite guidelines there clearly exists a discrepancy in work-up with IHC and imaging for this heterogeneous disease .
Similar to results of large prospective trial of molecular tumor profiling to determine tissue of origin in older patients with CUP, molecular tumor profiling on this cohort of AYA patients predicted biliary tract to be the most common putative site of origin . We showed that ToO results were compatible with the presumed primary diagnosis based on clinicopathologic findings in fewer cases than shown in prior studies . Molecular profiling has been utilized in CUP based on validation studies performed in metastatic cancers of known primaries [15–17]. Recent studies suggest ToO can provide a specific lineage diagnosis in many patients with poorly-differentiated neoplasms unclassifiable by standard pathologic evaluation, and has the potential to complement standard pathologic evaluation when IHC is inconclusive [18, 19]. In the absence of additional well designed prospective validation and outcomes-based research, the current consensus guidelines do not recommend gene expression profiling in the standard management of CUP . However, since studies indicate that there is a potential role of ToO testing in a subset of CUP; further studies are needed to assess the benefit of molecular assays in improving clinical outcomes in these CUP subsets.
Exploratory analysis showed patients undergoing definitive surgery or radiation had a quite robust median survival of 38.2 months compared to a survival of 15.4 months, 10.4 months and 6.1 months in patients receiving systemic chemotherapy with gemcitabine, fluorouracil and platinum/taxane-based regimens, respectively. The small sample size restricts evaluation of CUP subsets (e.g. those patients who present with nodal disease alone vs. osseous dominant vs. isolated carcinomatosis) and impact of specific chemotherapy doublets. Collaborative mutli-instituional databases are required to overcome this limitation in the study of CUP in AYAs.
The impact of ToO testing on survival outcomes in the AYA-CUP cohort in interesting but cannot be overemphasized. Patients who were tested did better than those who did not undergo testing and this likely represents a selection bias, such that a patient with poor expected outcome is unlikely to get molecular profiling.
Figs 1 and 2 describe patient cases that are typical for a CUP clinic. There are several questions that emerge e.g. in a patient with intestinal profile CUP, how best to interpret RAS testing? Patient in Fig 1 had IHC specific for lower gastrointestinal cancer (without a primary) with responses to the armamentarium of drugs used in colon cancer. Given the NRAS mutation, an EGFR inhibitor was not used. The case in Fig 2 describes the challenges of managing poorly differentiated neoplasms including non-specificity of IHC, discrepancy in IHC and ToO results and discussing this with young patients and their parents, and the ambiguity involved in the management of these very complex presentations.
Although this is the first study on this rare subset of patients, the small size of the cohort is a limitation and findings need corroboration in larger cohorts. Our study, as any other retrospective series, is also associated with certain drawbacks inherent to the nature of analyses, including selection, reporting (including missing data) and referral bias. Furthermore, the diverse diagnostic and treatment approaches, outside of our institution, can potentially confound these results. It is also important to note that favorable CUP subsets such as women with isolated adenocarcinoma involving the axillary lymph nodes, women with papillary serous adenocarcinoma of an unknown primary, squamous carcinoma of the cervical lymph nodes, undifferentiated or low grade neuro-endocrine carcinoma of unknown origin, poorly differentiated carcinoma of the midline concerning for extragonal presentation were excluded from this cohort due to referral patterns as these are best treated by site-specific recommendations. Therefore this study chiefly addresses the unfavorable subset. Nevertheless, this study is a first step highlighting the unmet need of investigations in this population.
Although, preliminary data has started to emerge regarding molecular profiling in CUP it is currently insufficient to envision personalization of therapy or introduction of targeted therapy [7, 21–23]. There is an urgent need to understand the role of “-omics” in CUP cancers and differentiate the biological dissimilarities between CUP in AYAs and adults. Methodical mutational analysis in various AYA-CUP subsets will help with understanding the biology and push the therapeutic envelope and allow these patients on biomarker matched clinical trials. Participation of AYAs with CUP in clinical trials should be encouraged to avoid prior experience and adverse impacts of low clinical trial accrual in this group [24, 25]. At this time whether patients will benefit from histology agnostic molecular-driven trials, such as the National Institute of Health MATCH study, remains to be seen, but we must offer our AYA-CUP patients the opportunity to enroll in these studies. Finally, as novel therapies are developed for known cancers, they will likely impact appropriate CUP subtypes. Over the next several years, we need to focus our efforts in refining AYA-CUP subsets and leverage selective genomics and proteomics techniques to eventually deliver validated new therapeutic approaches to our AYA-CUP patients.
In conclusion, CUP in AYAs is a challenging clinical entity associated with a morbid prognosis. Concerted research efforts are needed to tackle this orphan disease in this complex population.
Conceived and designed the experiments: KR GV. Performed the experiments: KR HM JLM AR GV. Analyzed the data: KR XL. Contributed reagents/materials/analysis tools: KR GV. Wrote the paper: KR HM JLM XL AR AM HW MJO GV.
- 1. Bleyer A, Barr R, Hayes-Lattin B, Thomas D, Ellis C, Anderson B, et al. The distinctive biology of cancer in adolescents and young adults. Nature reviews Cancer. 2008;8(4):288–98. pmid:18354417
- 2. Coccia PF, Pappo AS, Altman J, Bhatia S, Borinstein SC, Flynn J, et al. Adolescent and young adult oncology, version 2.2014. Journal of the National Comprehensive Cancer Network: JNCCN. 2014;12(1):21–32; quiz pmid:24453290
- 3. Rosenberg AR, Kroon L, Chen L, Li CI, Jones B. Insurance status and risk of cancer mortality among adolescents and young adults. Cancer. 2014.
- 4. Parsons HM, Harlan LC, Seibel NL, Stevens JL, Keegan TH. Clinical trial participation and time to treatment among adolescents and young adults with cancer: does age at diagnosis or insurance make a difference? Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2011;29(30):4045–53.
- 5. Bleyer A, Choi M, Fuller CD, Thomas CR Jr., Wang SJ. Relative lack of conditional survival improvement in young adults with cancer. Seminars in oncology. 2009;36(5):460–7. pmid:19835741
- 6. NIH-NCI LYAA. Closing the Gap: Research and Care Imperatives for Adolescents and Young Adults with Cancer: Report of the Adolescent and Young Adult Oncology Progress Review Group 2006 [updated 20068th March 2015]. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES: National Institutes of Health & National Cancer Institute and LIVESTRONG™ Young Adult Alliance]. Available from: http://planning.cancer.gov/library/AYAO_PRG_Report_2006_FINAL.pdf.
- 7. Varadhachary GR, Raber MN. Carcinoma of unknown primary site. The New England journal of medicine. 2014;371(21):2040.
- 8. Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet. 2012;379(9824):1428–35. pmid:22414598
- 9. Hainsworth JD, Rubin MS, Spigel DR, Boccia RV, Raby S, Quinn R, et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2013;31(2):217–23.
- 10. Lieu CH, Renfro LA, de Gramont A, Meyers JP, Maughan TS, Seymour MT, et al. Association of age with survival in patients with metastatic colorectal cancer: analysis from the ARCAD Clinical Trials Program. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2014;32(27):2975–84.
- 11. Culine S, Kramar A, Saghatchian M, Bugat R, Lesimple T, Lortholary A, et al. Development and validation of a prognostic model to predict the length of survival in patients with carcinomas of an unknown primary site. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2002;20(24):4679–83.
- 12. Hainsworth JD, Spigel DR, Clark BL, Shipley D, Thompson DS, Farley C, et al. Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial. Cancer journal. 2010;16(1):70–5.
- 13. Hainsworth JD, Daugaard G, Lesimple T, Hubner G, Greco FA, Stahl MJ, et al. Paclitaxel/carboplatin with or without belinostat as empiric first-line treatment for patients with carcinoma of unknown primary site: A randomized, phase 2 trial. Cancer. 2015.
- 14. Varadhachary GR. Carcinoma of unknown primary: focused evaluation. Journal of the National Comprehensive Cancer Network: JNCCN. 2011;9(12):1406–12. pmid:22157558
- 15. Varadhachary GR, Spector Y, Abbruzzese JL, Rosenwald S, Wang H, Aharonov R, et al. Prospective gene signature study using microRNA to identify the tissue of origin in patients with carcinoma of unknown primary. Clinical cancer research: an official journal of the American Association for Cancer Research. 2011;17(12):4063–70.
- 16. Greco FA, Spigel DR, Yardley DA, Erlander MG, Ma XJ, Hainsworth JD. Molecular profiling in unknown primary cancer: accuracy of tissue of origin prediction. The oncologist. 2010;15(5):500–6. pmid:20427384
- 17. Varadhachary G. New strategies for carcinoma of unknown primary: the role of tissue-of-origin molecular profiling. Clinical cancer research: an official journal of the American Association for Cancer Research. 2013;19(15):4027–33.
- 18. Greco FA, Lennington WJ, Spigel DR, Hainsworth JD. Poorly differentiated neoplasms of unknown primary site: diagnostic usefulness of a molecular cancer classifier assay. Molecular diagnosis & therapy. 2015 Apr;19(2):91–7.
- 19. Greco FA, Lennington WJ, Spigel DR, Hainsworth JD. Molecular profiling diagnosis in unknown primary cancer: accuracy and ability to complement standard pathology. Journal of the National Cancer Institute. 2013 Jun 5;105(11):782–90. pmid:23641043
- 20. NCCN. Occult Primary (Cancer of Unknown Primary) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)2015. Available from: http://www.nccn.org/professionals/physician_gls/pdf/occult.pdf.
- 21. Pentheroudakis G, Kotteas EA, Kotoula V, Papadopoulou K, Charalambous E, Cervantes A, et al. Mutational profiling of the RAS, PI3K, MET and b-catenin pathways in cancer of unknown primary: a retrospective study of the Hellenic Cooperative Oncology Group. Clinical & experimental metastasis. 2014;31(7):761–9.
- 22. Pavlidis N, Briassoulis E, Bai M, Fountzilas G, Agnantis N. Overexpression of C-myc, Ras and C-erbB-2 oncoproteins in carcinoma of unknown primary origin. Anticancer Res. 1995;15(6B):2563–7. pmid:8669824
- 23. Ross JS, Wang K, Gay L, Otto GA, White E, Iwanik K, et al. Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site: New Routes to Targeted Therapies. JAMA oncology. 2015;1(1):40–9. pmid:26182302
- 24. Bleyer A, Budd T, Montello M. Adolescents and young adults with cancer: the scope of the problem and criticality of clinical trials. Cancer. 2006;107(7 Suppl):1645–55. pmid:16906507
- 25. Bleyer A, Montello M, Budd T, Saxman S. National survival trends of young adults with sarcoma: lack of progress is associated with lack of clinical trial participation. Cancer. 2005;103(9):1891–7. pmid:15795902

domain: biology


|Publication number||US3566858 A|
|Publication date||Mar 2, 1971|
|Filing date||Nov 4, 1968|
|Priority date||Nov 4, 1968|
|Publication number||US 3566858 A, US 3566858A, US-A-3566858, US3566858 A, US3566858A|
|Inventors||Larson Stephen R, Sinclair John C|
|Original Assignee||Zenith Radio Corp|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (6), Non-Patent Citations (1), Referenced by (27), Classifications (9)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States Patent 72] Inventors Stephen R. Larson Evanston;
John C. Sinclair, Oak Park, Ill. 773,068
Nov. 4, l 968 Mar. 2, 1971 Zenith Radio Corporation Chicago, Ill.
[21 Appl. No.  Filed  Patented  Assignee [5 4] AN Tl-STUTTERING THERAPEUTIC DEVICE Audio An m1 n ier Pu 156 Shaping Circuit 23 Primary Examiner-Richard A. Gaudet Assistant Examinerl(yle L. Howell Attorney-John J. Pederson ABSTRACT: A therapeutic device which provides voice masking to assist a patient in overcoming a speech deficiency such as stuttering. A microphone, selectively responsive to the patients voice, receives his speech and converts it into electrical signals which are utilized to develop a control signal. An audio oscillator generates an audiofrequency pulsed wave which is varied in frequency in proportion to pitch changes in the patients voice by a circuit responsive to the control signal. An output transducer converts the audiofrequency pulsed wave into a corresponding sound wave which is applied to the patients ear. A switching circuit, also responsive to the control signal, enables application of the sound wave only while the patient is speaking or attempting to speak.
PATENTEU MAR 2 l97l Invenrors phen R. Larson John C. Sinclair AN TI-STUTTERING THERAPEUTIC DEVICE BACKGROUND OF THE INVENTION It is known that a persons speech deficiency, such as stuttering, is at least partially caused by the person hearing himself speak. Hence, devices to treat such a disorder have been developed which typically reduce the persons hearing response to his own voice by generating a masking signal. A conventional device of this nature uses a microphone to monitor the persons speech and develop a signal to trigger a soundproducing device to cause the latter to'deliver the masking signal while the person is speaking. Vented earpieces are used to couple the masking signal to the patients ear and permit him to hear others when he is not speaking. Thus, the person may use such a device and simultaneously carry on a normal conversation while he is overcoming his tendency to stutter.
The type of masking sound used in the conventional system may be a random sound also referred to as white noise. It is a sound composed of 'each frequency component in the audio frequency spectrum produced at random with approximately the same amplitude. Speech, on the other hand, is essentially composed of a fundamental frequency and higher harmonics thereof and occupies a relatively small portion of the audio frequency spectrum. Moreover, as the pitch of a persons voice changes so, naturally, does the fundamental frequency and its harmonics. Masking is accomplished by blocking the sound of the patients speech. In order to obtain sufficient amplitude for the frequency components of speech necessary to reduce a persons hearing response to his own voice and thereby obtain effective masking, a relatively large amplitude white noise signal is required. Thisnecessarily requires a large amount of amplification and, in the example of a wearable battery-operated device, greater battery drain and con- SUMMARY OF THE INVENTION In accordance with the invention, a new and. improved therapeutic system for assisting a patient to overcome a tendency to stutter, of the type comprising a microphone for monitoring the speech of the patient, a sound-producing device to be worn by the patient, and means for delivering a masking signal to the sound-producing device to cause the latter to reduce the patients hearing response to his own voice, comprises the improvement of providing means coupled to said microphone for effecting variations in the frequency of the masking signal in accordance with the variation in pitch of the patients voice.
BRIEF DESCRIPTION OF THE DRAWING The features of the present invention which are believed to be novel are set forth with particularity in the appended claims. The invention, together with further objects and advantages thereof, may best be understood by reference to the following description taken in connection with the accompanying drawing, the single FIGURE of which is a schematic diagram of a preferred embodiment of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT Referring to the FIGURE, an improved antistuttering therapeutic device includes a microphone which preferably is selectively responsive only to speech sound waves from a patient using the device. These sound waves may be received by placing such a microphone near the patients throat, substernal triangle, or other portions of the body where speech vibrations are prevalent. Using a selective microphone substantially eliminates the possibility of extraneous noises interferring with the operation of the device.
In general, the electrical signal output of the microphone 10 is coupled to an amplifier system 20 wherein the electrical signal is converted into a control signal which appears at terminal B. An oscillator circuit 50 generates an audiofrequency signal which is coupled to an amplifier circuit 60 wherein it is amplified to a level sufficient to operate output transducer 70 for subsequent application of the audio sound wave to the user's ears. The output-transducer 70 is also structured such that sounds other than the patients own voice are permitted to reach his ear so that the system does not interfere with his hearing when he is not talking. A switching circuit 40 is responsive to the control signalat terminal B for enabling operation of oscillator circuit 50 only while the patient is speaking.
In accordance with the invention, it has been found that greatly increased masking is obtained by employing a masking signal whose dominant frequency components follow the pitch variations in the patients speech. To this end, a circuit 30 is provided which is also responsive to the control signal at terminal B for effecting variations in the frequency of oscillation of oscillator circuit 50 in proportion to the changes in pitch of the patients voice. The frequency ,of the oscillator 50 may be any audiofrequency; but preferably it is made equal to the fundamental speech frequency. In addition, the output signal of the oscillator 50 is fashioned such that it is a pulsed signal wave in order to obtain substantial amounts of harmonic signal components. Thus, the output of transducer 70 is a masking sound of a fundamental frequency which follows the variation in the fundamental speech frequency resulting from changes in pitch. Moreover, by utilizing a pulsed signal wave for the masking signal, the higher harmonics of the fundamental frequency are produced and arealso varied in accordance with the variations in pitch of the patients voice. Thus, the masking sound comprises essentially the same dominant frequency components and is varied proportionally with the patients voice to achieve optimum voice masking. This is not to say, however, that the device reproduces the patients voice, which would be defeating its purpose, but rather it generates essentially the same dominant frequency components as those comprising the patients speech but in an unintelligible manner. In addition, increased efficiency of the output stage may be achieved because the pulsed signal wave may operate with a low duty cycle and still provide effective masking. Furthermore, it maintains optimum masking even as the pitch of the patients voice changes. To give a better understanding of the operation of the invention, a more detailed explanation of the circuit in the FIGURE follows below.
Referring again to the amplifying system 20, it is shown to comprise an audio amplifier 21, a pulse shaping circuit 22, a diode 23, and transistors Q and Q connected as a monostable multivibrator 24. Circuit 22 receives the amplified audio signals from audio amplifier 21 and produces a pulse train at terminal A of a frequency corresponding to the fundamental frequency of the patients voice. In this embodiment, circuit 22 produces a pulse train of a frequency equal to that of the fundamental frequency of the patients voice, although the advantageous results of the invention may still be at least partially achieved by using any desired proportional frequency relationship. Diode 23 transmits only the negative pulses appearing at terminal A to trigger multivibrator 24. Thus, the
multivibrator 24 oscillates at a rate corresponding to the fundamental frequency of the patients voice. The resulting output signal of multivibrator 24, appearing at terminal B, is a series of pulses of sufficient amplitude and width to operate circuit 30 and switching circuit 40.
In this embodiment, switching circuit 40 is in the form of a transistor 0 in series with a half-wave rectifying circuit consisting of diode 41, resistor 42, and capacitor 43. It is responsive to the signal at terminal B to turn on transistor Q and thereby enable operation of the oscillator circuit 50 by completing its energy source path from a supply potential V to ground. This controls the device so as to produce an output signal at the patients ears only while he is speaking. The time constant of resistor 42 and condenser 43 is preferably set at approximately 200 milliseconds to provide masking between normally spaced words while permitting the patient to hear environmental sounds when he is not speaking. A manual switch S is also incorporated in parallel with transistor to provide means for operating the device continuously (position 1) or automatically (position 2). Of course, the switching circuit is not limited to use with the oscillator. A similar circuit may be used in conjunction with the amplifier circuit 60 or the output transducer 70, for example, to achieve the same result.
Oscillator circuit 50 is an essentially conventional astable multivibrator 51 consisting of transistors Q and Q and associated biasing and timing circuitry. A variable resistor 52 is provided in the timing network so that the frequency of oscillation of the circuit may be adjusted to an appropriate nominal frequency in relation to the frequency range of the voice of the particular patient using the device. This pitch control may provide control of nominal frequency within the range from 75 to 250 hertz and permits persons, both male and female, having voices with different pitch characteristics to use the invention with equal benefit. The waveform of the output signal of this particular oscillator circuit is a low duty cycle (e.g., percent) rectangular wave. It therefore contains substantial amounts of the harmonic frequencies of the fundamental frequency. The invention is not, however, limited to this particular type of output signal as any signal having a relatively high harmonic content is sufficient.
Circuit 30 is a conventional RC differentiating network which responds to the essentially rectangular pulses at terminal B and develops very sharp transient pulses therefrom at terminal C. In accordance with the invention, the signal appearing at terminal C is coupled to the base of transistor Q through resistor 31. In operation, the free-running frequency of the multivibrator 51 is set to a frequency, depending on the pitch of the patients voice, lower than the patients fundamental voice frequency by pitch control 52 so that the pulse signal from terminal C overrides the voltage on the base of transistor 0 and thereby increases the frequency of operation of the multivibrator 51 to that of the fundamental voice frequency. Thus, the signal appearing at the output transducer 70 corresponds to the fundamental frequency and harmonics of the patients voice and automatically maintains this relationship even as the patients voice changes in pitch. Because the rectangular wave provides masking superior to that of prior devices using white noise masking signals, a low duty cycle may be used to thereby significantly lower the power requirements of the overall system, permitting more efficient battery use in a wearable device.
Thus the invention provides a new and improved antistuttering therapeutic device which operates more effectively and more efficiently then prior art devices. By providing a masking sound which follows the variations in pitch of the patients voice and by utilizing a signal with a relatively high harmonic content, optimum voice masking is achieved in a simple and efficient manner.
While a particular embodiment of the invention has been shown and described, it will be obvious to those skilled in the art that changes and modifications may be made without departing from the invention in its broader aspects, and, therefore, the aim in the appended claims is to cover all such changes and modifications as fall within the true spirit and scope of the invention.
1. In a therapeutic system for assisting a patient to overcome a tendency to stutter, of the type comprising a microphone for monitoring the speech of the patient, a sound producing device adapted to be worn by the patient, and means for delivering a masking signal to the sound-producing device to cause the latter to reduce the patients hearing response to his own voice, the improvement which comprises; means coupled to said microphone and to said masking-signal means for effecting variations in the frequency of said masking signal in accordance with variations in the pitch of the patients voice.
2. A therapeutic system as defined in claim 1, which further comprises means for maintaining the application of the masking sound for approximately 200 milliseconds after the voice of the patient ceases, thereby providing masking between normally spaced words while permitting the patient to hear environmental sounds when he is not speaking.
3. A therapeutic system for assisting a patient to overcome a tendency to stutter, of the type comprising a microphone for monitoring the speech of the patient and a sound-producing device adapted to be worn by the patient, and in which a masking signal is applied to the sound-producing device when the patient speaks to actuate the sound-producing device to at least partially override the hearing response of the patient to his own voice, the improvement which comprises; means coupled to said microphone and to said sound-producing device for developing a pulsed signal wave whose fundamental frequency component varies proportionally with variations in the pitch of the patient's voice for application as said masking signal to said sound-producing device.
4. A therapeutic device for providing voice masking to aidin the correction of a patients speech deficiency comprising:
a microphone for receiving speech sound waves and converting them into input electrical signals, said sound waves essentially comprising a fundamental frequency and harmonics thereof and being subject to frequency variations corresponding to changes in pitch of the patients voice;
signal generating means coupled to said microphone and responsive to said input electrical signals for developing a control signal;
oscillator means for generating an electrical signal having a predetermined audiofrequency of oscillation;
circuit means coupled between said signal generating means and said oscillator means and responsive to said control signal for varying said frequency of oscillation proportionally with said pitch changes;
output means coupled to said oscillator means for converting said audiofrequency electrical signal into an audio sound wave and adapted for applying said wave to the patients ear; and
switch means coupled to said signal generating means and responsive to said control signal for enabling said application of said audio sound waves.
5. A therapeutic device as defined in claim 4, in which said signal generating means comprises the series combination of a pulse shaping circuit and a monostable multivibrator coupled to said microphone and responsive to said input electrical signals for producing electrical pulses of a predetermined shape and of a predetermined frequency which varies proportionally with said variations of said fundamental frequency of said speech sound waves.
6. A therapeutic device as defined in claim 4, in which said oscillator means comprises an astable multivibrator having means for manually setting its nominal frequency of oscillation to thereby provide an audiofrequency signal containing said fundamental frequency and higher-frequency harmonic components thereof for optimum voice masking.
7. A therapeutic device as defined in claim 6, in which said circuit means comprises a differentiating network responsive to said control signal for developing transient pulses of a frequency corresponding to the fundamental frequency of said speech sound waves and applying said transient pulses to said astable multivibrator to override said frequency setting means and thereby automatically vary the frequency of the audiofrequency signal proportionally with the fundamental frequency variations of the speech sound waves.
8. A therapeutic device as defined in claim 4, in which said switch means comprises delay means for enabling said application for approximately 200 milliseconds following the cessation of said control signal, thereby providing masking between normally spaced words while permitting the patient to hear environmental sounds when he is not speaking.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US3043913 *||Nov 21, 1958||Jul 10, 1962||Auguste Tomatis Alfred Ange||Apparatus for the re-education of the voice|
|US3101081 *||Feb 15, 1961||Aug 20, 1963||Ile D Etudes Et De Brevets Mot||Apparatus for the conditioning of the auditory lateralization|
|US3101390 *||Jun 8, 1960||Aug 20, 1963||Ile D Etudes Et De Brevets Mot||Apparatus for audio-vocal conditioning|
|US3349179 *||Apr 8, 1964||Oct 24, 1967||Klein Marvin E||Anti-stuttering device and method|
|US3373508 *||Oct 29, 1964||Mar 19, 1968||Hc Electronics Inc||Teaching apparatus|
|GB1040001A *||Title not available|
|1||*||NATURE, Nov. 5, 1955, Vol. 176, pp 874 875, (copy in gr. 335, 35/35.3)|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US3773032 *||Dec 3, 1971||Nov 20, 1973||Technology Exchange Inc||Acoustical apparatus for treating stammering|
|US4063550 *||May 28, 1976||Dec 20, 1977||Tiep Brian L||Method and apparatus for treating bronchial asthma|
|US4143648 *||Apr 13, 1977||Mar 13, 1979||Behavioral Controls, Inc.||Portable therapeutic apparatus having patient responsive feedback means|
|US4421488 *||Mar 3, 1981||Dec 20, 1983||Paul Parlenvi||Aid for curing or mitigating stammering|
|US4464119 *||Nov 10, 1981||Aug 7, 1984||Vildgrube Georgy S||Method and device for correcting speech|
|US4662847 *||Nov 29, 1985||May 5, 1987||Blum Arthur M||Electronic device and method for the treatment of stuttering|
|US5478304 *||Nov 18, 1993||Dec 26, 1995||Webster; Ronald L.||Anti-sturrering device and method|
|US6231500 *||May 2, 1995||May 15, 2001||Thomas David Kehoe||Electronic anti-stuttering device providing auditory feedback and disfluency-detecting biofeedback|
|US6754632||Sep 18, 2000||Jun 22, 2004||East Carolina University||Methods and devices for delivering exogenously generated speech signals to enhance fluency in persons who stutter|
|US6944497||Oct 31, 2001||Sep 13, 2005||Medtronic, Inc.||System and method of treating stuttering by neuromodulation|
|US7258660||Sep 17, 2004||Aug 21, 2007||Sarfati Roy J||Speech therapy method|
|US7632225||Jun 27, 2005||Dec 15, 2009||Medtronic, Inc.||System and method of treating stuttering by neuromodulation|
|US7815597||Jun 27, 2005||Oct 19, 2010||Medtronic, Inc.||System and method of treating stuttering by neuromodulation|
|US7874977||Oct 15, 2004||Jan 25, 2011||Cochlear Limited||Anti-stuttering device|
|US9381110||Apr 30, 2014||Jul 5, 2016||Purdue Research Foundation||Method and system for training voice patterns|
|US9532897||Jul 16, 2014||Jan 3, 2017||Purdue Research Foundation||Devices that train voice patterns and methods thereof|
|US20060041184 *||Jun 27, 2005||Feb 23, 2006||Medtronic, Inc.||System and method of treating stuttering by neuromodulation|
|US20060041221 *||Jun 27, 2005||Feb 23, 2006||Medtronic, Inc.||System and method of treating stuttering by neuromodulation|
|US20060041242 *||Jun 27, 2005||Feb 23, 2006||Medtronic, Inc.||System and method of treating stuttering by neuromodulation|
|US20070010704 *||Oct 15, 2004||Jan 11, 2007||Dan Pitulia||Anti-stuttering device|
|US20100145134 *||Dec 2, 2009||Jun 10, 2010||Oticon A/S||Device for Treatment of Stuttering and Its Use|
|DE3146556A1 *||Nov 24, 1981||Jun 1, 1983||Georgij Sergeevic Vildgrube||Method and arrangement for improving speech|
|EP2193767A1 *||Dec 2, 2008||Jun 9, 2010||Oticon A/S||A device for treatment of stuttering|
|WO1981002513A1 *||Mar 3, 1981||Sep 17, 1981||P Parlenvi||Aid for curing or mitigating stammering|
|WO2002024126A1 *||Dec 18, 2000||Mar 28, 2002||East Carolina University||Methods and devices for delivering exogenously generated speech signals to enhance fluency in persons who stutter|
|WO2011022314A1 *||Aug 16, 2010||Feb 24, 2011||Purdue Research Foundation||Method and apparatus for increasing voice loudness|
|WO2012116015A1 *||Feb 22, 2012||Aug 30, 2012||Purdue Research Foundation||Method and system for training voice patterns|
|U.S. Classification||600/23, 434/185, 600/28|
|International Classification||A61F5/58, G09B19/04|
|Cooperative Classification||A61F5/58, G09B19/04|
|European Classification||A61F5/58, G09B19/04|


Base Weapon Damage
All Weapons Base 1d6+3 Physical Damage. If this is a Melee Weapon, Melee Damage is automatically converted into Physical Damage by default.
Choose a Weapon Type
All Weapons are custom built for or by the character. To begin, the character chooses a type of Weapon varying from the Race which created them.
Clockwork Weapon – 19ore
Dmg 5Sh//Ap -1//Acc 3//Mode SA//Shot 20
Pepper Weapon – 17ore
Dmg 5Sh//Ap -2//Acc 2//Mode FA//Shot 15
Fire Weapon – 20ore
Dmg 11burn//Ap 1Bashing//Acc 1//Mode SS//Shot 40
Force Weapon – 14ore
Dmg 9supp, ex//Ap 0//Acc 0//Mode SS//Shot 40
Laser Weapon – 18ore
Dmg 10burn//Ap 1//Acc 2//Mode SS//Shot 45
Pulse Weapon – 14ore
Dmg 7//Ap -1//Acc 0//Mode BF//Shot 30
Rail Weapon – 24ore
Dmg 6pr//Ap 4//Acc 2//Mode SS//Shot 50
Chain Weapon – 11ore
Dmg 6//Ap -1//Acc -2//Mode FA//Shot 25
Thundering Weapon – 11ore
Dmg 7ex//Ap -1//Acc -1//Mode SA//Shot 50
Choose Weapon Class
Weight 4, Requires 1 Hand.
Increase Damage by 3
Reduce Speed by 1
Increase Cost by 6
Requires 2 Hands
Increase Damage by 6
Reduce Speed by 3
Increase Cost by 12
Requires 2 Hands
If the Character moves before firing this Weapon, they suffer a -2 Accuracy penalty. The Character may not move after Firing this Weapon.
Constructing and Upgrading
Next, customize the Weapon with different Upgrades and Properties. A Weapon may not be equipped with more than their Rating in Upgrades nor with an Upgrade with higher Rating than the Weapon itself. Further, Weapons and Upgrades with Ratings greater than 2 are automatically RESTRICTED. Properties gained from Weapon Upgrades do not stack.
Smart Targeting – 4ore
Increases Awareness by 1.
Enhanced Sighting – 4ore
Reduce Accuracy penalties by 1.
Heat Sink – 4ore
Reduce Shot requirement by 5 per Rating.
Frictionless Materials – 7ore
Reduce Shot requirements by 3 per Rating. Increase Accuracy by 1.
Power Rail – 5ore
Increase Damage by 1. Increase Shot Requirement by 3.
Extended Rail – 5ore
Increase Accuracy by 1. Increase Shot Requirement by 3.
Scram Rail – 5ore
Increase Armor Penetration by 1. Increase Shot Requirement by 3.
Recoil Damper – 5ore
Reduce penalties to Accuracy from Fire Modes by 1.
Suppressor – 4ore
Reduce bonus provided to Awareness for shooting this Weapon by 1.
Flashlight – 3ore
Targets in front of the Weapon suffer from Bright Light Intensity within Close Range.
Light Materials – 4ore
Reduce Weapon Weight by half.
Range Compensator – 8ore
Reduce Range Penalties by 1.


text:
The U.S. Bureau of Land Management, which manages federal land and its resources, recently announced its intention to sell oil and gas leases in June for parcels totaling more than 43,000 acres in Alabama’s national forests. Most of the parcels are in the Talladega National Forest in central and eastern Alabama, including Calhoun County. One parcel is in Conecuh National Forest in the southern part of the state.
Some areas proposed for leasing contain or are near environmental resources such as the Pinhoti National Recreation Trail, the Chinnabee Silent Trail, Talladega Scenic Drive, Cheaha Mountain and Rebecca Mountain. They also contain waterways including Choccolocco, Cheaha and Shoal creeks, along with other tributaries to the Coosa, Tallapoosa, and Cahaba rivers.
Attempts Monday to reach the Bureau of Land Management were unsuccessful, as were attempts to reach a spokesperson for the National Forests of Alabama under the U.S. Department of Agriculture Forestry Service.
The Southern Environmental Law Center, a regional nonprofit conservation organization that uses the law to support environmental issues in the Southeast, submitted a letter of protest Monday to the Bureau of Land Management, demanding Alabama’s national forests be taken off the list for use in oil and gas drilling. The letter argues the BLM is relying on outdated environmental analyses done by the U.S. Forest Service in 2004 as part of the revised management plan for Alabama's national forests. It states that among other deficiencies, the analyses fail to assess the environmental impacts of drilling using high-volume hydraulic fracturing, known as “fracking.”
Fracking is a form of gas drilling in which millions of gallons of water and chemicals are injected underground to fracture rock called shale and to release natural gas trapped by the rock. The technique has garnered controversy in recent years due to its supposed harmful effects on groundwater.
“This could be of a particular concern to Anniston, as some of the parcels are adjacent to its reservoir,” said Sarah Francisco, national forests and parks program leader for the Southern Environmental Law Center.
According to BLM’s sales notice, a parcel runs near the Anniston Water Works and Sewer Board’s Shoal Creek Watershed, a reservoir the city is not currently using but has slated for future use. Jim Miller, general manager for Anniston Water Works and Sewer Board, said he is not sure fracking would have much of an impact on the reservoir.
“Fracking generally isn’t an issue since it’s done deep in subterranean rock layers,” Miller said. “It might have more of an impact on aquifers like Coldwater Spring.”
Coldwater Spring is Anniston’s main source of drinking water.
Miller said it was possible gas and oil drilling in general could impact the city’s water.
“The devil is in the details of what they do out there,” Miller said. “You want to be careful about erosion and runoff. We’d have to take a hard look at it and protest it if we need to.”
The protest letter also argues the bureau’s decision to include national forest land for leasing is illegal and should not be permitted.
“We believe it is illegal because the bureau has not considered all environmental impacts required under the National Environmental Policy Act,” Francisco said.
Francisco said the bureau had not shown that enough would be done to protect endangered species in the national forests.
"The Bureau of Land Management is proposing a massive intrusion into Alabama's national forests without properly analyzing the potential impacts and without providing sufficient information to the public,” said Keith Johnston, managing attorney for the Birmingham office of the Southern Environmental Law Center. “Some of the areas they propose leasing for oil and gas development are near some of the most popular destinations in the forests.”
Francisco added that the Talladega National Forest would be hurt by more than just the act of drilling.
“It’s not just the wells, but the roads and other infrastructure that must be added,” Francisco said. “It’s major industrial activity that usually includes an open pit for wastewater and is often a 24/7 operation. This could destroy wildlife habitats.”
Staff writer Patrick McCreless: 256-235-3561. On Twitter @PMcCreless_Star


text:
Kiss Me, Kate--Still a Robustly Entertaining Show
By Joseph Cervelli
While it is hard to forget the wonderful 1999 revival of Cole Porter's masterpiece "Kiss Me, Kate" the new production presented by The Roundabout Theatre Company at Studio 54 is just as robustly entertaining. There may be a few stumbles along the way but when you have the incomparable Kelli O' Hara in the title role with her rapturous voice (just try not to stand on your feet and applaud at her "So in Love") all is well with this joyous show.
The book by Sam and Bella Spewack is still intact, although there is some additional material added by Amanda Green to give it a bit more of a modern feel. But no worries. She knows that to make any major changes would be criminal to say the least and her light touches make it work and should appeal to all audiences.
The story has never been "Kate's" strongest asset for that belongs to the buoyant score by Porter. The book has the two leads O'Hara as Lilli Vanessi and Will Chase (he starts out a bit shaky but then zeroes into the role) as her egocentric actor ex-husband Fred Graham appearing in a touring company in a production of "The Taming of the Shrew" which resembles their own life together. While Graham has a roving eye he mistakenly sends flowers and a love note to Lilli who still has strong feelings for him even though she is involved with a pompous military man Harrison Howell (Terence Archie.) When she finds out that Graham is seeing someone else she decides to take the fighting moments in "Shrew" to a new level of kicking him every chance she gets. While Scott Ellis' direction is every bit as energetically entertaining as you would expect from this skilled director some of those scenes head too far into slapstick.
There is a subplot which works perfectly thanks to Corbin Bleu as the gambler/hoofer Bill Calhoun. With his megawatt smile Bleu lights up the stage. While it is hard to forget Michael Berresse's amazing climbing in his "Bianca" number in the previous revival Bleu makes the song his own with his tapping up the stairs and on the ceiling. He is in love with the slightly dippy showgirl Lois Lane (a fine Stephanie Styles.) Her "Always True to You in My Fashion" is a standout.
The one number that falls surprisingly flat is the crowd pleasing "Brush Up Your Shakespeare" with Porter's brilliantly clever lyrics. Sung by the two hoodlums First Man (John Pankow) and Second Man (Lance Coadie Williams) the song never takes off. Both actors seem never to grasp the wittiness of the lyrics and seem to rush through it which is a big disappointment.
O'Hara is not only in magnificent voice but plays the humor just right without going over the top as in the savvy "I Hate Men." Chase does seem to be trying too hard in the beginning of the show (his voice is always top notch) but does far better in the second act.
Warren Carlyle still one of the best choreographers around never fails to disappoint with his bouncy, inventive dance routines.
The stalwart set designer David Rockwell has created a colorful set (love the sight gag with the clouds disappearing showing the next town the traveling troupe is touring in) and Jeff Mahshie's costumes are perfect.
Having the stage bathed in red lighting during the high powered "Too Darn Hot" is a tribute to veteran lighting director Donald Holder's expertise.
With O'Hara in the title role, that incomparable score, and a fine cast it is hard not to have a most fun filled evening at this revival.
Tickets are available at Studio 54 254 West 54th Street or by calling 212.719.1300.
PHOTOS: JOAN MARCUS

domain: entertainment


text:
Published by Cipher-Naught, July 2015
About the Book:
Beards, brothers, and bikers! Oh my!
Identical twins Beau and Duane Winston might share the same devastatingly handsome face, but where Beau is outgoing and sociable, Duane is broody and reserved. This is why perpetually level-headed Jessica James has been in naïve and unhealthy infatuation with Beau Winston for most of her life. Whereas Duane and Jessica have always been adversaries. She can't stand him, and she's pretty sure he can't stand the sight of her...
But after a case of mistaken identity, Jessica finds herself in a massive confusion kerfuffle. Jessica James has spent her whole life paralyzed by the fantasy of Beau and her assumptions of Duane's disdain; therefore she's unprepared for the reality that is Duane's insatiable interest, as well as his hot hands and hot mouth and hotter looks.
When Jessica finds herself drawn to the man who was always her adversary, how much of her level-head heart is she willing to risk?MY TAKE:
Truth or Beard is book #1 in the Winston Brother's series. Each book is a standalone, full length (110k words), contemporary romantic comedy novel, and follows the romantic exploits and adventures of one of the six Winston Brothers.
What fun! I'm not really a "beard" kinda gal, but Penny Reid's sassy writing made me rethink a whole lot of my previous assumptions. Fast-paced, action-packed and filled with heart, humor and a good dose of snark, I was sucked right into this beautiful Tennessee landscape and settled in for the long haul.
Jessica is a hot mess of contradictions, in a good way. She's a planner and a calculus teacher, back in her small town working at her old high school to pay off her student debt. Sensible, smart, and solid. And yet she makes no secret of her plans to travel the world and see it all.
When we meet her in the first chapter, she's headed to a community center Halloween party as a "sexy Gandalf" with full beard and thigh grazing shift, having modified her costume after school hours were over. She ends up in a dark corner making out with the guy she's had a crush on for years. Except.. it turns out it's not him, it's his identical twin whom she holds in utter disdain. Or thought she did. Turns out, not so much.
As it turns out, even though Jessica thought she had a crush on Beau, it's Duane who she's been paying attention to and cataloging for... well, all her life. She knows how he likes his coffee and how he got the scar over his eyebrow... all the little things you notice about someone. And the heat she feels every time he looks at her has little to do with being annoyed by him and a whole lot to do with the electricity bouncing between them that explodes off the page when they kiss.
Duane Winston - Oh, I don't like the name, but I loved the complicated, intuitive, thoughtful man. He's had a thing for Jessica James for years. Years. Long enough to build up all kinds of unrealistic expectations and fantasies of white picket fences and happily ever afters. Turns out he and Jessica share that planning and dreaming trait - but have opposite (and role reversed, in the romance universe) plans and dreams.
Throw in a bunch of small town twists, a local motorcycle club, and Jessica's ornery older brother who takes his police badge a little too seriously, and you've got one fun romp of a story that keeps the pages turning despite whining kids and piles of laundry. Or maybe that's just my house. Either way, Reid is a talented author who knows her way around both character development and action packed plots. This is the second book of hers I've read (totally recommend Neanderthal seeks Human, published 2013) and I may have to use those Amazon gift cards I got for Christmas to order up a few more. 5 stars of fun and sizzle.
Grab your copy on AMAZON

domain: library