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Blog Archives
Paying Tolls with a New Car
In case you missed it, the California Department of Motor Vehicles announced a new Temporary License Plate Program starting January 1, 2019. The new law (AB 516) states:
"This law requires licensed California dealers, of new and used vehicles, to attach temporary paper license plates on a vehicle at the point of sale if that vehicle does not display license plates previously issued by the DMV. The temporary license plates contain a unique number and expiration date. No vehicle can be driven off the dealership lot without the temporary license plate affixed to it unless it already has issued plates.."
If you recently purchased a new car and would like to drive on The Toll Roads, here are some helpful travel tips:
I bought my car prior to January 1, 2019 and I have paper plates from the car dealership. How can I pay tolls?
In order to drive The Toll Roads, a vehicle without a license plate must have a FasTrak transponder properly mounted to the windshield. It is illegal to drive The Toll Roads in a vehicle that does not have license plates or a FasTrak transponder. CHP patrol our roads to enforce this law.
I bought a car after January 1, 2019 and have a temporary license plate. How can I pay tolls?
Good news! Driving The Toll Roads with new temporary plates is easy. If you have a FasTrak or ExpressAccount account, simply add the temporary plate to your account and drive. If you have a FasTrak transponder, placing it on the windshield will not guarantee that tolls will be charged to your account; adding the temporary plate to your account will avoid the chance of fees or penalties.
If you don't have an account, you can pay tolls within five days before or after driving The Toll Roads by using the Pay Toll option found at TheTollRoads.com and on our free app for Apple and Android devices.
Does the temporary license plate number have to match the permanent license plate number?
No. Temporary license plates will contain a unique alpha/numeric configuration. When you receive your permanent plates in the mail it is important to add them to your existing FasTrak or ExpressAccount and remove your temporary plate to avoid the chance of fees or penalties.
To see all new laws affecting California drivers click here.
Happy 20th Birthday!
Twenty years later, the 241 Toll Road continues to provide congestion relief for thousands of drivers
The year is 1998 – Bill Clinton is President, Titanic dominates the box office, gas is $1.06 a gallon, Google was just founded, and the first Harry Potter book is released. But, more importantly, a 24-mile segment of the 241 Toll Road, connecting the 91 Freeway to Irvine, opens. This segment provided drivers an alternative route to the congested 55 Freeway when traveling between Orange and Riverside Counties.
At the time, the project was one of the largest design/build contracts in U.S. history and was Orange County's largest transportation project in a decade. Twenty years later, more than 60 million tolls are collected on the 241 Toll Road each year and it continues to provide congestion relief for hundreds of thousands of drivers every day.
We dug deep in our archives for some great construction photos and here are 20 fun facts to celebrate the 241 Toll Road's 20th birthday.
The Transportation Corridor Agencies (TCA) – a joint powers authority including the Foothill/Eastern Transportation Corridor Agency and San Joaquin Hills Transportation Corridor Agency – was formed in 1986 to address Southern California's booming population, worsening traffic conditions and diminishing government funds.
- Due to a lack of state funding, private toll revenue bonds and development impact fee revenue was used to finance and construct Orange County's Toll Roads. The majority of the tolls collected pay back the debt issued to fund construction.
- The Toll Roads were constructed with wildlife in mind. Natural travel patterns of deer and other wildlife were tracked and monitored to determine the paths they most frequently used. The Toll Roads then built wildlife undercrossings at the locations where the animals travel the most, allowing them to move safely and quickly from point A to point B. One of the busiest wildlife undercrossing in Southern California is under the 241 Toll Road.
- TCA was one of the first agencies in the state to use the design-build method for construction of public roads. The approach combined design and construction simultaneously to reduce the construction duration and cost.
- The first 3.2-mile segment of the 241 Toll Road opened in October 1993 near Foothill Ranch and spanned from Portola North to Portola South. Click here to view when other segments of The Toll Roads opened.
- The legislation that gave TCA permission to collect tolls mandated that tolls be collected electronically, which gave birth to FasTrak®. FasTrak is a system that uses a transponder to exchange information with a roadside computer, automatically deducting tolls from the user's prepaid account as the vehicle passes through the toll points without slowing.
- Beyond Orange County, you can also use your FasTrak transponder for instant access to all of California's toll roads, lanes and bridges – even the Golden Gate Bridge.
- TCA was the first toll road operator in the nation to offer a free mobile app for toll account management in 2012. To date, the app has been downloaded more than 1.3 million times to help customers manage their account or pay a toll from their smart phone or tablet.
- During construction of the 241 Toll Road construction site, a TCA contracted biologist rescued a baby golden eagle that was found lost and weak in a temporary construction reservoir. The eagle was nursed back to health and released back into the wild.
- A secret hollow rock, known as Bennet Rock, is perched at the top of a slope just north of the 241 Toll Road bridge over Santiago Creek. The legend is that it was constructed in honor of Jerry Bennet, TCA's Chief Engineer at the time, who wanted to preserve the natural and unique outcropping along the right-of-way. The rock didn't survive the earthwork, but the contractors had it recreated just for Jerry.
- The iconic red rock formations on the northbound side of the 241 Toll Road as you approach the 91 Freeway are nicknamed the "Badlands," as they are reminiscent of the famous South Dakota badlands.
- Santiago Creek Bridge is a 90-foot high bridge and sits at about 735 feet above sea level. The Windy Ridge Toll Point is the highest elevation point along the 241 Toll Road at 1,286 feet.
- Irvine Lake, located near Santiago Canyon and the 241 Toll Road, is a reservoir that was built between 1929 and 1931 and provides drinking water to Villa Park and parts of Orange.
- The 241 Toll Road has three tunnels constructed through the cut and cover process. There are three tunnels on The Toll Roads. The one seen here is located at the northbound 133/241 interchange.
- There are four cell phone towers along the 241 Toll Road. Each tower reaches a height of 105 feet and they were intentionally designed to blend in with the natural landscape.
- There are five mainline toll points on Orange County's Toll Roads. Tomato Springs Toll Point, closest to Lake Forest, was named after the location of a 1912 posse shootout that took place nearby.
- The 51-miles of Toll Roads – State Routes 73, 133, 241 and 261 – represent 20 percent of Orange County's highway system and make up the largest network of toll roads in California.
- Tolls are collected three ways on Orange County's Toll Roads – FasTrak, ExpressAccounts® and one-time online payments.
- On average, 1,000 new FasTrak accounts and ExpressAccounts are opened every day. As of Oct. 31, 2018, the number of open accounts totaled more than 1.37 million.
- The Toll Roads and saving time go hand-in-hand. A weekday rush hour trip from the El Toro "Y" to the Orange/Riverside County Line saves drivers 15 minutes via the 133 and 241 Toll Roads compared to using the 5 and 55 freeways.
With more than 320,000 daily trips on Orange County's Toll Roads, that's 320,000 less trips on the already congested 5, 55, and 405 freeways; thereby improving mobility for everyone – even those who don't use it! The 73, 133, 241 and 261 Toll Roads continue to be the easiest and most predictable way to get to and through Orange County. Happy birthday – and thank you for providing drivers a choice for over 20 years.
Cruising the Corridor in the Summer of 1996
I drive to and from Anaheim Hills and Irvine on The Toll Roads every day. I love my congestion-free drive. But before you begin rolling your eyes at the gal who works for The Toll Roads, I've learned new reasons and meaning to love and appreciate my drive.
My commute is a free-flowing 25 minutes and provides ample stress-free time to call my Mom from my Bluetooth. I check-in; ask about her day, and how Dad and "the boys" (their three dogs) are doing. Our chats are always engaging and a relaxing way to end my work day, but one thing that never fails is Mom's daily question, "are you driving the corridor today?" to which I always reply, "Mom, it's called The Toll Road" (as if a teenager is scolding her Mom for not using cool lingo).
This week marks 20 years since the Transportation Corridor Agencies (TCA) opened the first phase of the San Joaquin Hills Transportation Corridor, known to most people as the 73 Toll Road. And in celebrating this milestone, the word corridor brings new meaning to me, my job and a drive that I don't take for granted.
In the summer of 1996, I didn't yet have my driver's license, but Mariah Carey's "Always Be My Baby" was a summer chart topper and "Macarena" was one of the coolest songs out there; Independence Day with Will Smith was also a box office hit. The Toll Roads – 51 miles of open road that serve as alternatives to Orange County's congested freeways – have always been part of my driving experience, and anyone who's been driving in Orange County since the late 90's, knows no different. But to my Mom, who still calls them "the corridors," they provide a much-needed sigh of relief to Orange County's gridlock and enhanced the county's transportation landscape while also preserving open space.
On July 20, 1996, TCA invited residents of Orange County to Cruise the Corridor as they celebrated the opening of the first phase of the San Joaquin Hills Transportation Corridor. I found the invitation and program as I dug through our archives. In the summer of '96, thousands of Orange County residents joined TCA for a fun run to experience the road before it opened to traffic and to celebrate 20 years of planning and nearly four years of construction. The new road was the first seven-mile stretch of a corridor that would ultimately take drivers 15 miles from Laguna Niguel to Newport Beach, providing a new transportation alternative to the 5 and 405 freeways.
Leading up to the opening of the new San Joaquin Hills Transportation Corridor, Mom read headlines about TCA's strong environmental programs used throughout construction and the innovative financing and planning to make the roads possible. The term "corridor" has always stuck with her. Back in the 90's, "corridor" was a modern term commonly used to describe multiple modes of transportation to move people, such as highways, rail and buses.
The San Joaquin Hills Transportation Corridor was the start of a link between South County and coastal cities and it has proven to be a valuable route. Although over time the name changed to the 73 Toll Road to reflect what the public called the new route, to Mom, it will always be the "corridor."
In celebrating this milestone, I've learned to appreciate how the "corridor" enhanced the quality of life in Orange County by cutting commute times, reducing rush-hour frustration and making Southern California destinations more accessible. In those 20 years while the county continued to grow and expand, the "corridor" has always served the same purpose – trips on the 73 Toll Road have more than doubled in 20 years, logging nearly 31 million transactions last year. It's hard to imagine what traffic would be like in Orange County without the 73 Toll Road!
So on my drive home when I call Mom tonight, I'll smile when she asks if I'm driving the corridor and I'll proudly respond, "yes, Mom, I'm cruising the corridor home today."
The Toll Roads: Where to Go & What to Know
School is out, bags are packed and summer vacation has officially begun. But before you hit the road for your family staycation or road trip, here's a list of the five things you need to know to beat the summer heat and SoCal traffic:
Don't Forget to Pack Your FasTrak® Transponder – The 73 Toll Road is a popular route for drivers traveling between Los Angeles and San Diego and the 241 Toll Road is a popular route to get to and from the Inland Empire, mountains and deserts to Orange County's beaches. Be sure you've packed your FasTrak transponder before hitting the road. Because not only can you use FasTrak to pay tolls when driving The Toll Roads in Orange County but it also works on all of California's tolled bridges, lanes and roads.
Paying Tolls Without an Account? There's An App for That. – The Toll Roads recently released a new and improved mobile app allowing you to pay tolls on the 73, 133, 241 and 261 Toll Roads in the palm of your hand if you don't have an account. Download the latest version of The Toll Roads' app by searching "the toll roads" in the Google Play and Apple App Stores and enjoy a stress-free drive in Orange County. You can also compare account types and sign up with the updated app.
Paying Tolls With a Rental Car is Now Easier than Ever – The Toll Roads have partnered with most major rental car companies to simplify toll payments by allowing tolls to be charged directly to your credit card through rental car agreements. The new rental car toll payment program, eligible only on State Routes 73, 133, 241 and 261 in Southern California, eliminates the chance of a rental car customer receiving a Notice of Toll Evasion after they return their rental vehicle. Visit our rental car page to learn more about options for rental car drivers, including steps to take if you're already a FasTrak or ExpressAccount® customer.
Calculate Your Tolls – Want to know what the cost is for a particular trip? Check out our online toll calculator to easily calculate your toll by selecting the road you will drive; your entry and exit points (choose "unknown" if you are not sure); how you will pay; and type of vehicle. Rates to drive on Orange County's Toll Roads will increase slightly on Friday, July 1, from one cent to 14 cents, depending on the location and time of travel. The toll calculator webpage also features a downloadable map and rate card.
Hosting Family & Friends? –If you're hosting out-of-town guests or renting or borrowing a vehicle, be sure to temporarily add the vehicle's license plate number to your FasTrak or ExpressAccount so they can drive The Toll Road without worrying to pay online.
Safe travels and enjoy your drive on The Toll Roads.
Community Ascertainment Study Findings
In April 2015, the Foothill/Eastern Transportation Corridor Agency (F/ETCA) retained Sharon Browning and Associates to conduct a community ascertainment study to gather input and gain insight on how best to collaborate to address regional mobility challenges in South Orange County. The scope of the study was designed to develop an understanding of the community's definitions of the problem; priorities to be considered in proposing solutions; and preferences for process, planning and decision making.
In-person, confidential interviews were conducted with 45 residents and active community leaders — excluding elected officials — in cities and unincorporated areas in South Orange County. Topics of discussion included Interstate 5 (I-5) mobility challenges, describing the problem, exploring solutions including a need or no need for a State Route 241/I-5 connections, who should lead planning efforts and how planning should be led and exploring the need for consensus.
Below is a brief summary and analysis of the findings that will assist in developing a plan for achieving a consensus.
- The study analyzed the contents of each interview to identify areas of high agreement and areas of lack of agreement, in order for the F/ETCA to focus on areas of agreement in future regional traffic solution planning, particularly around relieving traffic on the I-5 corridor.
- The environment of the study included discussion around existing I-5 construction, the Avenida La Pata extension, and the local culture, political perspective, values and practices of each community.
- The study found high agreement in the community that excessive traffic congestion exists along the I-5, north and south from Oso Parkway to Cristianitos Road on weekends, during peak usage times and when accidents occur. The study confirmed the community is greatly concerned about this problem because of its negative impacts on quality of life.
- The study revealed the community is looking for increased engagement and choices at the local level.
- The study revealed that the community may not expect 100 percent consensus, rather an open, collaborative problem-solving process led by elected officials with community input.
A full report of the community ascertainment study may be viewed in full here.
After cash toll collection ended on Orange County's toll roads on May 14, a program was implemented to ease drivers' transition to the new all-electronic toll collection system. The transition program — originally put in place through the long Labor Day weekend — has been extended as The Toll Roads continue to evaluate data about usage, payments, feedback from customers and reports from customer service representatives.
"We will keep the transition program in place while we monitor how drivers are using the roads as summer winds down, tourism lightens and many people get back to their commuting routines," said Mike Kraman, acting CEO of The Toll Roads. "We also want to keep the transition program in place as we make improvements to our customer service functions to better serve our customers."
As part of the transition program:
• Penalty fees for first-time violations are waived if the tolls incurred are paid within 30 days of receiving a notice of toll evasion. Approximately 40 percent of violation notices are sent to people who have never before received a violation notice.
• Drivers without a pre-established tolling account can pay tolls online within seven days after driving the roads using the One-Time-Toll™ payment option. One-Time-Toll was developed to be used within 48 hours of driving the roads. Data is being reviewed to determine if the One-Time-Toll payment timeframe will be extended permanently.
The following improvements have been (or are being) implemented:
• Additional road signs have been installed. There are now 414 signs on the roadway informing drivers that they are on a tolled road; that cash is not accepted; that tolls can be paid electronically via a pre-established account or online using the One-Time-Toll payment option; and that a violation will be issued if tolls are not paid.
• Information about the closure of cash booths and how to pay online has been added to changeable message signs located on freeways leading to The Toll Roads.
• Information about the penalty relief for first-time violations is inserted into first-time violation notices. The notice also includes information about how to sign up for a FasTrak® or ExpressAccount® for future trips.
• To support the conversion, 14 employees were added to the customer service department. Six additional temporary customer service representatives have been added and 20 more are in the process of being added.
• Forty-six additional phone lines are being added to the customer call center. To accommodate callers.
• Adjustments have been made to information on the website to address common questions.
• Outreach programs to the general public; Spanish-speaking community; tourism industry; rental car agencies; seniors; college campuses; and military are being expanded and revamped as needed.
Approximately 250,000 people drive The Toll Roads every day as a way to avoid traffic congestion and save time. A majority of customers — 91 percent — pay with either a FasTrak, ExpressAccount or with the One-Time-Toll online payment feature. Since May 14, 65,269 ExpressAccounts® have been opened and 440,267 drivers have paid using One-Time-Toll™
Five ways to pay tolls on The Toll Roads:
1. FasTrak: Establish a prepaid account, pay tolls that are $1 less than all other drivers pay and receive a transponder that allows you to pay tolls electronically on every tolled bridge, lane and road in California.
2. Charge ExpressAccount: Establish an account with no prepayment. Drive The Toll Roads and your daily tolls are charged to your credit card. You cannot use this account to pay tolls on any other bridge, lane or road.
3. Invoice ExpressAccount: Establish an account with no prepayment. Drive The Toll Roads and, at the end of the month, receive an invoice for your accumulated tolls. This account includes an invoice fee. You cannot use this account to pay tolls on any other bridge, lane or road.
4. Prepaid ExpressAccount: Establish a prepaid account. Drive The Toll Roads and tolls are deducted from your prepaid account. You cannot use this account to pay tolls on any other bridge, lane or roads.
5. One-Time-Toll payment option: Drive The Toll Roads and within 48 hours after your drive, use our website or free app to pay your toll(s) with a credit card.
Beginning Wednesday, May 14 at 12:01 a.m., cash toll collection will cease on The Toll Roads in Orange County, making travel faster and more convenient for the more than 250,000 weekday commuters who choose The Toll Roads.
"Tuesday will be the final day to pay with cash on The Toll Roads," said Lisa Bartlett, chairwoman of the Foothill/Eastern Transportation Corridor Agency. "The removal of cash tolls is a trend throughout the tolling industry and we've surveyed our cash customers to provide new electronic payment options that will work for them."
In January, the Transportation Corridor Agencies (TCA), which operates The Toll Roads, introduced four new ways to pay tolls to replace cash toll collection. Along with the hugely-popular FasTrak® payment method, the three new ExpressAccount™ types and the new One-Time-Toll™ option make the drive on The Toll Roads fast and convenient.
More than 82 percent of transactions are already paid electronically using a FasTrak or ExpressAccount, while 13 percent are cash transactions.
"We want all customers to experience the benefits of a free-flowing drive that our FasTrak and ExpressAccount customers enjoy," said Rush Hill, chairman of the San Joaquin Hills Transportation Corridor Agency. "If they haven't signed up for a FasTrak or ExpressAccount, now is the time to ensure you always have options."
Tomorrow is also the final day of work for toll attendants, who have worked at the Toll Roads toll plazas since the first plaza opened in 1993. All toll personnel (toll attendants, lead toll attendants, managers, assistant managers, etc.) are contract employees of Central Parking System, the largest parking management firm in the country, operating approximately 700 parking locations in Orange and Los Angeles counties alone. CPS will seek to find alternate employment options for these employees in other company positions in Southern California.
"We honor the service they've provided our customers and they have been part of the success of The Toll Roads," said Chairman Hill.
In just six days cash toll collection will cease on The Toll Roads. Are you ready? If you have FasTrak® or AN ExpressAccount™ the answer is yes.
If you currently pay with cash when you drive State Routes 73, 133, 241 and 261, now is the time to decide how you will pay after 12:01 a.m. on May 14.
There are five ways to pay tolls on The Toll Roads: FasTrak, three new ExpressAccount types and the new One-Time-Toll option. Click here for information about the different account options and to learn which one is right for you.
TCA is offering new FasTrak and ExpressAccount customers a free week of nonstop driving as soon as they establish an account at thetollroads.com (PROMO CODE: FREETOLL). The offer ends May 11.
Will you join the 450,336 people who have a FasTrak account or the 69,619 who have an ExpressAccount?
Haven't experienced a nonstop, stress-free commute in Orange County in a while? Now's the perfect time to give The Toll Roads a try for an entire week — for free.
"We want every motorist in Orange County to experience what 250,000 weekday drivers already know — there's no stop and go on The Toll Roads when you have FasTrak® or an ExpressAccount™," said Lisa Telles, The Toll Roads' chief communications officer.
In anticipation of The Toll Roads removing cash toll collection on May 14 at 12:01 a.m., TCA is offering new FasTrak and ExpressAccount customers a free week of nonstop driving as soon as they establish an account at thetollroads.com (PROMO CODE: FREETOLL). The offer ends May 11.
In January, The Toll Roads introduced more ways to pay tolls to replace cash toll collection. Along with the hugely-popular FasTrak payment method, the three new ExpressAccount types make the drive on The Toll Roads fast and convenient — and most importantly — nonstop. With FasTrak and ExpressAccount, all tolls are collected electronically while motorists travel at highway speeds.
For more information about the different account options and which one is right for you, please visit thetollroads.com. An ExpressAccount can only be used on The Toll Roads (State Routes 73, 133, 241 and 261) and the toll is, on average, 20 percent higher than the toll paid by a FasTrak customer.


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Wang M, et al. ASH 2017:155
Efficacy and safety of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma in the phase II ACE-LY-004 study
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is efficacious in patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL); however, it has been associated with toxicities such as atrial fibrillation, bleeding, and infections.1,2 Off-target activities of ibrutinib may contribute to the incidence of these toxicities.3 Acalabrutinib is a highly selective, potent, covalent BTK inhibitor with minimal off-target activities in preclinical studies.4,5 At the 2017 ASH Annual Meeting, a phase II study evaluated the efficacy and safety of acalabrutinib monotherapy in patients with R/R MCL.6
Study design
- The ACE-LY-004 study enrolled patients between March 12, 2015, and January 5, 2016, at 40 centres across 10 countries.
- A total of 124 patients with R/R MCL who received 1–5 prior therapies were enrolled.
- Patients received 100 mg acalabrutinib twice a day in 28-day cycles until disease progression.
- Primary endpoint was overall response rate (ORR) by investigator assessment based on the Lugano classification.
- Secondary endpoints included ORR by independent review committee (IRC) assessment, duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, pharmacokinetics (PK), and pharmacodynamics.
- Exploratory endpoints included time to response and IRC-assessed ORR per the 2007 International Harmonization Project (IHP) criteria.
- Data cutoff was February 28, 2017.
- Inclusion criteria were:
- Confirmed MCL with translocation t(11;14)(q13;q32) and/or overexpressed cyclin D1;
- Relapsed after or refractory to 1–5 prior treatments;
- Measurable nodal disease (≥1 lymph node ≥2 cm in longest diameter);
- Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2; and
- Age ≥18 years.
- Exclusion criteria were:
- Significant cardiovascular disease (uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within six months of screening, any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval >480 ms);
- Concomitant use of warfarin or equivalent vitamin K antagonists; and
- Previous treatment with BTK inhibitors.
Key findings
Baseline characteristics and disposition
- Median age was 68 years (range: 42–90).
- The majority of patients were male (80%) with an ECOG PS ≤1 (93%), Ann Arbor stage IV disease (75%), and extranodal disease (73%).
- Patients had received a median of two prior therapies.
- The majority of patients had previously received rituximab as a single agent or as part of a regimen (95%).
- The majority of patients had previously received a CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-based regimen (52%).
- At a median follow-up of 15.2 months, 56% of patients remained on study therapy.
- Of the 54 patients (44%) who discontinued acalabrutinib, reasons for discontinuation were:
- Disease progression (n = 39);
- Adverse event (AE) (n = 7);
- Receipt of stem cell transplant (n = 5);
- Lost to follow-up (n = 1);
- Withdrawal of consent (n = 1); and
- Patient decision to stop treatment (n = 1).
- AEs leading to discontinuation occurred in one patient each and were aortic stenosis, diffuse large B-cell lymphoma, blood blister and petechiae (in a patient with grade 3 acute coronary syndrome treated with clopidrogel), dyspnea and leukostasis syndrome, noncardiac chest pain, pulmonary fibrosis, and thrombocytopenia.
- Acalabrutinib PK parameters indicated rapid absorption and elimination, and low potential for accumulation.
- Acalabrutinib dosed at 100 mg twice a day (bid) resulted in a median BTK occupancy of 99% four hours post dose and 95%–97% before next dose.
- IRC-assessed ORR and complete response (CR) using the Lugano classification were 80% and 40%, respectively. (Table 1)
- A high concordance was observed between investigator- and IRC-assessed ORR and CR (91% and 94%, respectively).
- IRC-assessed ORR and CR by 2007 IHP criteria were 75% and 30%, respectively.
- ORR was consistent across all prespecified subgroups. (Figure 1)
- No differences were observed by sex, race, Ann Arbor stage, tumour bulk, or prior lenalidomide exposure.
- Most patients experienced a reduction in lymphadenopathy (94%).
- Median time to response was 1.9 months (range: 1.5–4.4).
- Initial response was achieved by the end of Cycle 2 in the majority of responders (92%).
- Median DOR has not been reached, and the 12-month DOR rate was 72% (95% CI: 62–80).
- Median PFS and OS have not been reached. (Figure 2)
- Most common AEs are summarized in Figure 3.
- Serious AEs (SAEs) occurred in 48 patients (39%).
- SAEs reported in ≥2 patients included:
- Pneumonia (n = 5, 4%);
- Anemia (n = 4, 3%);
- General physical health deterioration (n = 3, 2%);
- Sepsis (n = 2, 2%);
- Tumour lysis syndrome (n = 2, 2%); and
- Vomiting (n = 2, 2%).
- One grade 3 gastrointestinal (GI) hemorrhage occurred in a patient with a history of GI ulcers.
- One grade 5 AE (aortic stenosis) occurred in a patient with a history of aortic stenosis (not treatment related).
- No cases of atrial fibrillation were observed.
- Grade 3/4 cardiac AEs included:
- One grade 3 acute coronary syndrome (treatment related);
- One grade 3 acute myocardial infarction (not treatment related); and
- One grade 4 cardiorespiratory arrest (not treatment related).
- Any grade and grade 3/4 infections occurred in 53% and 13% of patients, respectively.
- Bleeding events occurred in 31% of patients and were all grade 1/2, with the exception of the grade 3 GI hemorrhage.
Key conclusions
- Acalabrutinib 100 mg bid demonstrated compelling efficacy and a differentiated safety profile, thus providing an alternative therapeutic option for patients with R/R MCL.
- Responses were durable, and the majority of the most common AEs were grade 1/2.
- There were few discontinuations due to AEs (6%).
- No atrial fibrillation was observed and the rate of grade ≥3 hemorrhage was low (1%).
- The PK and selectivity profiles of acalabrutinib allowed twice-daily dosing with minimal off-target effects while achieving near complete and continuous BTK inhibition over time.
References: 1. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013;369(6):507–16. 2. Imbruvica [package insert]. Sunnyvale, CA: Pharmacyclics, LLC; 2017. 3. Stephens DM, Spurgeon SE. Ibrutinib in mantle cell lymphoma patients: glass half full? Evidence and opinion. Ther Adv Hematol 2015;6(5):242–52. 4. Byrd JC, Harrington B, O'Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374(4):323–32. 5. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther 2017;363(2):240–52. 6. Wang M, Rule S, Zinzani PL, et al. Efficacy and safety of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma in the phase 2 ACE-LY-004 study. ASH Annual Meeting Abstracts 2017:155.


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12 Things Dad Taught Us About Money
Want to hear a money-related dad joke? (The answer is always yes.)
Anyone who thinks talk is cheap must not be paying his teen's phone bill.
Want another? (Of course.)
You're spending so much money on coffee each month, it looks like your budget got mugged.
Mugged. Get it? Oh man.
But seriously, dads give us a ton of punny jokes and grilling tips, but they also pass down loads of wisdom. In honor of Father's Day, we want to look into some of the dadisms many of us grew up hearing and see how they relate to budgeting. Here are 12 things Dad taught us about money.
1. "Money doesn't grow on trees."
Well, we could get technical and talk about how paper is made from trees, but we won't go there. We will go where Dad was sending us: You can't just walk outside and pluck bucks from tree limbs. Use your limbs and get to work.
2. "Sleep on any big purchase."
You know what being impulsive does? For Romeo and Juliet, it led to their early demise. Don't be like Romeo and Juliet. Don't rush into big purchases. Let the first impulse simmer down by taking at least one night to think before you buy.
3. "Leave room in your budget to help others."
Marie Kondo has created quite the catchphrase: Does it spark joy? Well, this dad tip proves he knew about sparking joy in a different way before Kondo came on the scene. Research shows giving to others boosts your own happiness.1 Help others. Help yourself. That's a win-win from Dad.
4. "Be thrifty, not a scrooge."
It's smart to put time, thought and effort into saving money. But hoarding treasure like Smaug in The Hobbit or Mr. Krabs in Spongebob Squarepants is just too far. Don't let your thrifty ways keep you from sparking that just-mentioned joy in giving. And don't let it keep you from enjoying and feeling secure in the life you have now.
5. "Always live below your means."
When you spend less than you make, you can use that extra money to make your money goals happen—like saving up for emergencies, crushing debt, investing for retirement, paying off your house early, etc. These things aren't doable when you're sending all the money that's coming in right back out again! Live below your means.
6. "Don't take money advice from broke people."
It makes such good sense. However, if someone was broke and made a proven plan to get out of that situation, that's different. That's Dave Ramsey. We love him. We'll take his advice all day long.
In fact, the advice means more because he knows what it feels like to hit rock bottom and climb back up again. That's who you take advice from. The climbers. The achievers. Not the broke.
7. "Hard work is hard work."
Okay. Read it again. It's not a typo or accidental repetition. It's truth. But there's payoff. So work hard, and don't expect great things to come easily.
8. "Waste not, want not."
Maybe our dads came up with this one by watching their moms rinse out gallon food storage bags and reuse them. Or maybe by seeing their dads fix the busted toaster instead of chucking it in the trash. Whatever taught our dads this phrase, it's one we could all stand to put in play far more often. Waste less stuff—and save more money.
9. "Save for a rainy day."
Why? Because it rains. We cannot predict what emergencies will come, but we can predict they will come. So, we're financially ready for them with emergency funds. Hey, rain—I can pay cash for a light sprinkle or a downpour. I'm ready!
10. "Learn the power of the word no."
Because it's a powerful word. With money, we need to know how to say no to ourselves and to our immediate wants. Because delaying gratification for now will bring an incredible payoff later.
11. "If you don't need it, it's not a good deal."
Yes, Dad. We shouldn't buy a second air fryer—even if it's on sale. Even if it's a "steal of a deal." Because all it's stealing is . . . our money. If we don't need it, spending money on it isn't actually saving money. It's wasting it.
12. "Beware financial opportunities that seem too good to be true."
"Because they probably are," Dad warned us. Get-rich schemes are just that—schemes. Getting rich takes time.
This reminds us of another dadism: Anything worth doing is worth doing right. It's worth the time and effort to budget, get out of debt, save up money, and build wealth.
So tell that "you can be a millionaire in three easy steps" plan it's not your thing, and tell budgeting it is your thing. Might we suggest EveryDollar for those budgeting needs? Okay. Suggest it we do.
Hey, Dad. Thanks. Thanks for playing catch, or driving us to all those flugelhorn lessons, or teaching us the Pythagorean theorem so we could pass geometry. And thanks for taking the time to give us those words of wisdom that we can now use to make wise money choices on our own.


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Inner Strength Products - Summer Tank Top
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Warning: these fit a bit on the small side, you might want to go a size up.
Proudly made in Canada


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Are you free from depression, anxiety, excessive stress, addictions, and other psychological problems?
- If yes, then you are much more able to live your life to the fullest.
- If no, there is something you need to modify or else it will modify you into something you would never like to happen.
" An individual's mental health can also impact physical health and poor mental health can lead to problems such as substance abuse and depression. "
Being mentally fit and healthy is achieving physical as well as mental fitness and well-being. It is that level of health with the absence of mental illness.
According to the World Health Organization (WHO), mental health includes the total well-being of being perceived self-efficacy, autonomy, competence, inter-generational dependence, and self-actualization of one's intellectual and emotional potential, among others.
In other words, mental health is the combination of physical, social, intellectual and emotional well-being affecting the way we do think, feel, act, work, and love.
Both mental and physical health are interlinked with each other. A patient with physical illness is more likely to get acquired with severe mental disorders as well. They are more likely to get involved with anxiety, loneliness, depression, etc.
Why it is important to be mentally fit?
Serious mental disorders are more common nowadays. It must be cured as soon as possible to get rid of various bad impacts over our mind and body.
Being mentally fit strengthens our ability to :
- Handle the natural stress of life.
- Realise, discover and grow to our full potentiality.
- Work productively and opt-in making good life choices.
- Maintain healthy and meaningful relationships with others.
Mental health is everything for a good and happy life. Here is how to be mentally fit and healthy and boost your life to the next level.
1. Exercise Your Body And Brain Regularly.
Carrying on regular exercise both for body and brain can take your mental fitness to the next level. Studies showed that cardiovascular exercise increases the release of "feel good hormones" which improves memory and mood. In addition, meditation and yoga can deliver a great boost to the mental wellbeing.
You can also opt for regular brain activities like puzzles, crosswords, soduku, chess, taking classes, executing challenges and also going for some virtual mind challenging computer games.
2. Eat And Stay Healthy.
Try to eat healthy foods like almonds, nuts, berries, bananas, eggs, milk, tomatoes, soybeans, peas, fish, etc. Food with essential Vitamin B-12 and fatty acids including Omega-3 must be consumed in a balanced diet and this is highly recommended.
Choose a hygienic place to stay along with healthy food. Think, work and stay healthy in order to be in a peaceful mind with the perfect mental wellbeing.
3. Take Deep Sleep Regularly.
Try to maintain a regular cycle of deep sleep for at least eight to nine hours a day. Poor sleep will link you to physical problems such as weekend immune system and mental health issues like stress, anxiety, and depression. Adjustment of light, noise, and temperature in the bedroom during sleep can incredibly help you for taking and holding on a good deep sleep.
4. Always Try To Be Happy And Joyful.
Being joyful and happy is an excellent health booster. Always, try to keep a smile on your face. Having good and open laughter will surely boost and strengthen your mental health and fitness. Be happy and enjoy your life giving a refreshment to your mind and body.
5. Spending Time With Amazing People You Like.
Try to cultivate your friends and family who will appreciate, support and love you. Spend time with these amazing people you like and they will provide you with entertainment, emotional wellbeing, and the bond of togetherness that nothing in this world can provide you with.
6. Try To Work On A Hobby Or Activity And Express Yourself.
Try to accept, express, explore and include yourself with regular activities and hobbies you like. This will help you to stay engaged and happy. Hobbies can help you overcome stress and increase your self-esteem and confidence.


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One of the nation's most recognisable and memorable wrestlers, Tony 'Banger' Walsh spent his career at the forefront of a wrestling craze in the UK. Entering onto the scene fit, young and more than a little handy, Tony had found his place in show business. A compelling after dinner speaker and entertainer, Tony describes to audiences how he rose to the top of his game and appeared in front of millions on television each week.
Learning to fight in the way of a wrestler, Tony became part of Joint Promotions wrestling portfolio, fighting the likes of Big Daddy, Tony became known for his entertaining style of fighting and natural ability to get a crowd excited. Walsh soon began to realise that wrestling was not based on the best man winning, and fights were often prearranged and the result decided before bouts even began. During talks as an after dinner speaker, Tony portrays the controversy behind the scenes of his sport and how to he came to act on what he found.
With the intensity of wrestling beginning to take a toll on Tony's health. After losing his sister in a car crash, Tony was shocked of the lack of support and sympathy from the wrestling world. With his career soon to be over thanks to the toll the sport had taken on his body, Tony decided to expose the injustice of wrestling to the public.
Ousting the fixers, ring rats and hypocrisy of the sport, Tony led the crusade of wrestlers who had suffered in the business. An exciting and interesting speaker, Tony experienced every aspect of wrestling and saw the business for what it really was. During talks, guests can experience what it felt like to stand in front a crowd to go and wrestle every week in the knowledge of your actions being broadcast to millions.
Contact the Champions Speakers agency to book Tony Walsh for your event today. Simply call a booking agent on 0207 1010 553 or email us at firstname.lastname@example.com for a free quote.


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And you expect me to trust you, and believe this?
"Almost Sold Out"
- Comment • 2
And you expect me to trust you, and believe this?
Marketing spin to tug at your human instinct of scarcity and compell you to take action by booking that reservation NOW.
This has been implemented by many travel outlets in recent years. Some even tell you "100 people are looking at this property right now" or "50 people like you have booked this today".
It's comical in my opinion but hey if it works for them then they will continue to market like this in the future.
Emotional selling is powerful and it works.
Now book that fantastic vacation you always dreamed about and rightly deserve. For a limited time, book now and receive 750 bonus points for your stay. Elect to go green and get another 500 bonus points per day. Use your new Marriott Rewards visa card and earn 6x points. But hurry, get that LTPP status before it's too late.
Love it.....


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Water is a fundamental human right
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Infertility, ectopic pregnancy, and chronic abdominal pain are frequent complications of genital infections with Chlamydia trachomatis. In an attempt to produce a vaccine to protect against this pathogen we purified and refolded the C. trachomatis mouse pneumonitis (MoPn) major outer membrane protein (MOMP). This preparation, mixed with Freund's adjuvant using vortexing or sonication, was used to immunize BALB/c mice that were subsequently challenged in the upper genital tract. Vaginal cultures were taken on a weekly basis, and mice were mated 6 weeks after the challenge. Gels of the vortexed MOMP showed a predominant band with a molecular size of 62 kDa and weaker bands at 42 and 132 kDa, while the sonicated MOMP had a single band with a molecular size of 42 kDa. Following immunization with these two preparations, strong humoral and cell-mediated immune responses were detected in the mice inoculated with the vortexed MOMP. On the other hand, mice immunized with the sonicated MOMP had a strong humoral immune response but a relatively weak cell-mediated immune response, as determined by a T-cell lymphoproliferative assay and level of cytokine production by splenocytes. Vaginal cultures showed that the mice immunized with the vortexed MOMP were significantly protected, as determined by a decrease in the number of animals with positive cultures, the length of time the mice shed viable organisms, and the number of inclusion-forming units recovered per mouse. Animals immunized with the sonicated MOMP, on the other hand, showed a weaker level of protection based on the same three parameters. After mating, the number of fertile animals and number of embryos per mouse were significantly higher for the mice immunized with vortexed MOMP, but not for the mice immunized with sonicated MOMP, compared to those of the control groups. In conclusion, immunization with a purified and refolded preparation of the C. trachomatis MoPn MOMP confers a significant level of protection in mice against a genital challenge.
Infections due to Chlamydia trachomatis impose a significant medical and economical burden throughout the world (12, 38, 54). In areas with poor hygienic conditions, infections with this bacterium result in trachoma, the most common cause of preventable blindness in the world (12,38). In addition, throughout the world this pathogen is one the leading causes of sexually transmitted diseases (12, 38, 42,54). The acute genital infection generally subsides, but in some patients it may result in long-term sequelae. In females, among the long-term sequelae infertility, ectopic pregnancy, and chronic abdominal pain are relatively frequent (55, 56). Effective antimicrobial therapy is available to treat infected patients. This approach, however, has not been effective at controlling infection by this organism. There are several reasons for this disappointing outcome (25, 42). On one hand, a majority of the genital infections in women are asymptomatic, and thus patients do not seek treatment. In addition, in patients that are symptomatic, by the time the antimicrobial therapy is implemented permanent damage may have already occurred. Routine screening, followed by adequate therapy, in certain populations at high risk can decrease the overall prevalence of the disease, but this approach is temporary and can be practically applied only to limited groups. Thus, if we want to control the diseases produced by this pathogen the most effective approach will be to engineer a vaccine.
Attempts to implement a vaccine using whole organisms forC. trachomatis infections have a long history (8,13, 41, 53). Four or five decades ago most efforts focused on developing a vaccine against trachoma using viable or inactivated whole organisms (13, 41, 53). More recently, adoptive immunization with dendritic cells pulsed ex vivo with inactivated whole chlamydial organisms has also been used as an experimental model to define the parameters of protection (19, 45). Several conclusions resulted from the earlier studies (13). The vaccine trials showed that an effective, although short-lived, protection could be achieved if the patients were immunized with sufficient antigen of the serovar that they were going to be subsequently exposed to. On the other hand, patients inadequately immunized suffered a hypersensitivity reaction when reexposed toC. trachomatis. This last observation has been interpreted as possibly an immune reaction to a chlamydial component, maybe the 60-kDa heat shock protein, that cross-reacts with some human antigen(s) (20). This possibility gave impetus for the development of a subunit chlamydial vaccine.
A total of 15 human serovars of C. trachomatis have been described (52). The trachoma biovar includes 12 serovars, A through K plus Ba, and the lymphogranuloma venereum group consists of the L1, L2, and L3 serovars. The A through C serovars have been isolated mostly from trachoma cases, while the D through K serovars mainly cause genital infections. The mouse pneumonitis (MoPn) biovar is the only isolate of C. trachomatis so far recovered from mice (24). The grouping ofC. trachomatis isolates into distinct serovars appears to be based mainly on the differences in the amino acid sequence of the variable domains (VD) of the major outer membrane protein (MOMP) of this organism (10, 43). The MOMP is surface exposed, accounts for over 60% of the mass of the outer membrane, and has been shown to induce neutralizing antibodies (5, 41, 53). These characteristics have made the MOMP the preferred candidate for a subunit vaccine (10, 41, 53). In our laboratory we have utilized the C. trachomatis MoPn model, since this serovar, as a natural murine pathogen, can infect the genital tract of mice and produce a pathology that closely mimics that found in humans (27, 46). Here we show that vaccination with a highly purified preparation of the MOMP that was refolded in an attempt to reestablish the conformation of the native epitopes was able to protect mice against a genital challenge.
Organisms.The C. trachomatis MoPn biovar (strain Nigg II) was purchased from the American Type Culture Collection (Manassas, Va.) and grown in HeLa 229 cells (27). The elementary bodies (EB) were prepared as described by Caldwell et al. (5). The organisms were frozen at −70°C in SPG (0.2 M sucrose, 20 mM sodium phosphate [pH 7.4], and 5 mM glutamic acid).
Preparation of the C. trachomatis MoPn MOMP. C. trachomatis MoPn grown in HeLa 229 cells was washed with 10 mM phosphate-buffered saline (PBS), pH 7.4, and centrifuged and the pellet was treated with DNase (31). Following centrifugation the pellet was resuspended in 0.2 M phosphate buffer, pH 5.5, containing 0.001 M concentrations (each) of EDTA and phenylmethylsulfonyl fluoride (PMSF) and was extracted with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate (CHAPS; Calbiochem-Novabiochem Corp., San Diego, Calif.) and Zwittergent 3-14 (Z3-14; Calbiochem-Novabiochem Corp.) as previously described (31). The MOMP was recovered in the supernatant and purified using a 1-cm by 35-cm hydroxylapatite column (5). Fractions containing the MOMP were pooled, run on a 5 to 20% gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and stained with silver and Coomassie blue (Bio-Rad, Hercules, Calif.). In addition, an N-terminal amino acid analysis was performed on the purified MOMP by the core facilities at the University of California, Irvine.
The MOMP was refolded by dialysis against 0.1 M phosphate buffer, pH 7.8, containing 0.001 M EDTA, 0.002 M reduced glutathione, 0.001 M oxidized glutathione, and 0.05% Z3-14 at room temperature at a protein concentration of 30 to 150 μg/ml (16). The MOMP was concentrated and fixed with 20% glutaraldehyde for 2 min at room temperature, and subsequently 2 M glycine was added to stop the reaction (47). Before inoculation, the preparation was concentrated using Centricon-10 filters and dialyzed against a solution containing 0.02 M phosphate buffer, pH 7.4, 0.15 M NaCl, and 0.05% Z3-14.
Animal immunization and challenge protocols.Seven- to 8-week-old BALB/c female mice (H-2d) were obtained from Simonsen Laboratories (Gilroy, Calif.). All animal protocols were approved by the University of California, Irvine, Animal Care and Use Committee.
Mice were immunized intramuscularly (5 μg/mouse) and subcutaneously (5 μg/mouse) with purified, refolded, and glutaraldehyde-fixedC. trachomatis MoPn MOMP that was mixed with complete Freund's adjuvant by vortex (vortexed MOMP), and they were boosted twice at 2-week intervals with the same dose of the MOMP preparation in incomplete Freund's adjuvant (31). Another group of mice was immunized with the same MOMP preparation that was mixed with Freund's adjuvant by sonication (sonicated MOMP) on ice with three bursts of 10 s each at high output using a Braun-Sonic-2000 apparatus (B. Braun Instruments, Burlingame, Calif.). Negative controls were inoculated in a similar manner, except ovalbumin was used. As a positive control, mice were immunized once intranasally with 104 inclusion-forming units (IFU) ofC. trachomatis MoPn. An uninoculated, nonchallenged control group was mated and kept in the vivarium under the same conditions to determine the normal fertility of this strain of mouse (27).
Two weeks after the last boost the mice were challenged in the left ovarian bursa with 105 IFU of C. trachomatis MoPn, while the right ovarian bursa was inoculated with mock-infected HeLa 229 cell extracts processed as the EB (27, 46, 50). Vaginal swabs were collected and cultured at 7-day intervals for a period of 6 weeks after the genital challenge as described previously (27). All experiments were repeated.
Immunoassays.Vaginal secretions and blood were collected before each immunization, and antibody titers were determined using an enzyme-linked immunosorbent assay (ELISA) as follows (27). Multiwell plates (96 flat-bottom wells; Corning Glass Works, Corning, N.Y.) were coated overnight with 1 μg of purified C. trachomatis MoPn EB per well. Serial dilutions of the serum samples were added to each well, and the plates were incubated for 2 h at 37°C. The antigen-antibody reaction was detected by adding horseradish peroxidase (HRP)-conjugated goat anti-mouse antibodies. The following class or subclass-specific antibodies were used: immunoglobulin G (IgG), IgG1, IgG2a, IgG2b, IgG3, IgA, and IgM (Southern Biotechnology Associates, Inc., Birmingham, Ala.). The reaction was measured at 405 nm using an ELISA reader (Bio-Rad Corp.). The substrate, 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic) acid (ABTS) was used for color development.
In vitro neutralization assays were performed using HeLa 229 cell monolayers as previously described (31). Briefly, 104 IFU of C. trachomatis MoPn was added to serial dilutions of the serum made with 5% guinea pig serum in PBS. After incubation for 45 min at 37°C, the mixture was inoculated in HeLa 229 cells by centrifugation. Following 24 h of incubation at 37°C the monolayers were fixed and stained with a rabbit polyclonal anti-C. trachomatis MoPn serum and a goat anti-rabbit peroxidase stain. The neutralization titer of a serum sample was the dilution that yielded 50% neutralization over the control serum.
Western blots were performed using nitrocellulose membranes as previously described (31, 39). Briefly, C. trachomatis MOMP was loaded on a 7.5-cm-wide mini slab-gel and resolved by 10% tricine SDS-PAGE. Serum samples, diluted 1:100 with PBS–0.005% Tween 20, were incubated for 2 h at room temperature, and then the strips were treated with a 1:500 dilution of HRP-conjugated goat anti-mouse IgG and the bands were visualized with 4-chloro-1-naphthol.
To assess the specificity of serum antibodies with regard to epitopes within the MOMP, serum samples were used to probe octameric peptides representing this protein. The peptides were synthesized with a kit (Cambridge Research Biochemicals Inc., Wilmington, Del.) (11, 31). Goat anti-mouse IgG1 or IgG2a (Southern Biotechnology Associates, Inc.) conjugated to HRP were used as second antibodies, and ABTS was the substrate utilized. The ELISA was repeated twice, using sonication in hot SDS and 2-β-mercaptoethanol to remove the antibodies between assays.
The lymphoproliferative assay was performed as previously described (27, 31). Spleens from two mice from each group were harvested, and single-cell suspensions were prepared to enrich for T cells using a nylon wool column. Using a fluorescence-labeled monoclonal antibody to CD3+ (GIBCO-BRL, Grand Island, N.Y.), close to 90% of the suspension was found to be T cells. Antigen-presenting cells were prepared by irradiating (3,300 rad of137Cs) unseparated spleen cells and incubating them with various concentrations of C. trachomatis MoPn EB. The enriched T-cell suspensions were cultured in 96-well plates at a concentration of 2 × 105 cells per well in 0.2 ml of RPMI 1640 supplemented with 10% fetal bovine serum. The lymphocytes were cocultured for 5 days with 1.2 × 105 antigen-presenting cells with or without antigen and stimulated with C. trachomatis MoPn EB. Concanavalin A was added to some wells as a positive control. At the end of the fourth day of incubation, 1.0 μCi of [methyl-3H]thymidine (47 Ci/mmol; Amersham, Arlington Heights, Ill.) in 25 μl of RPMI 1640 was added to each well and the uptake of the [3H]thymidine was measured.
Levels of gamma interferon (IFN-γ) and interleukin 4 (IL-4) were determined by using a commercial kit (Endogen, Cambridge, Mass.) with supernatants from splenic T cells stimulated as described above and collected at 48 h of incubation (28).
Fertility studies.Six weeks after the intrabursal challenge, groups of four female mice were housed with a proven breeder male mouse for a maximum of 18 days and the pregnancies were assessed by measuring the weight of each mouse (27). Animals that had gained 5 to 10 g of weight by or before 18 days postmating were considered pregnant and were euthanized, and the number of embryos in each uterine horn was counted. After the first mating the female mice that did not gain weight were mated a second time with male mice that had successfully mated with another group of female mice and were monitored as described previously (27). All the animals that had not gained weight were euthanatized 25 days from the start of the second mating. The number of embryos in each uterine horn was counted when the mice were killed.
Statistics.Statistical analyses were performed with the Statview software package on a Macintosh computer. The two-tailed unpaired Student's t test, the Mann-Whitney's U test, and the Fisher's exact test were employed to determine the significance of the differences between groups.
Characterization of the vaccine candidate preparations.The purity of the MOMP preparation, following the hydroxylapatite column, was first assessed by gel electrophoresis and amino acid sequencing. As shown in Fig. 1, only one band, corresponding to the C. trachomatis MoPn MOMP, was detected on a gradient gel stained with silver. By N-terminal amino acid analysis only the expected sequence, L-P-V-G-N-P, of the mature MoPn MOMP was obtained, indicating a greater than 99% purity of the protein. Figure 2A shows a Coomassie blue-stained SDS-PAGE of the folded C. trachomatis MOMP that was vortexed (lane 2) or sonicated (lane 5) and run under nonreducing conditions. The folded MOMP was also boiled for 10 min (lane 6), boiled for 10 min in the presence of 30 mM dithiothreitol (DTT) (lane 3), or treated with 30 mM DTT but not boiled (lane 4). Sonication and boiling of the folded MOMP under reducing or nonreducing conditions resulted in a predominant single band with an apparent molecular size of approximately 42 kDa. Under nonreducing conditions or reducing conditions but not boiling there is a prominent band of 62 kDa and faint bands with approximate molecular sizes of 42 and 132 kDa. The 62- and 132-kDa bands most likely represent homopolymers of the MOMP not linked by disulfide bonds, since boiling, without a reducing agent, resulted in a single band of 42 kDa. Figure 2B shows a Western blot of the C. trachomatis MoPn MOMP under boiled-reduced and nonboiled-nonreduced conditions probed with serum from mice immunized with the vortexed and sonicated MOMP preparations. Under reduced conditions only one band is detected with a molecular size of 42 kDa, while in addition to the 42-kDa band there is a band at 62 kDa, with faint bands above and below it under nonreduced conditions. The lack of an identifiable band at 132 kDa may be due to the poor transfer of large-molecular-size components during blotting. Alternatively, a paucity of antibodies was elicited by this antigen or epitopes to which antibodies were formed were partially blocked by the conformation of the 132-kDa molecules. Western blots probed with monoclonal antibody MoPn-40 to a linear epitope on VD1 appeared similar to those reacted with serum from mice immunized with vortexed or sonicated MOMP. A faint band corresponding to the molecular size of the lipopolysaccharide (LPS) could be observed when the Western blots of the MOMP preparation were performed using low dilutions of the immune serum (data not shown).
Immune response following vaccination with the MOMP.An antibody response was detected in serum and vaginal samples 2 weeks following the initial immunization with MOMP. Antibody titers continued to rise until the day before the intrabursal challenge (Table1). At that point the total IgG and IgA antibody titers in serum of the mice immunized with the vortexed MOMP were 12,800 and 1,600, respectively, while in the vaginal wash the IgG titer was 100 and the IgA titer was 50. Animals immunized with the sonicated MOMP had IgG and IgA titers in serum of 218,000 and 4,050, respectively, while in the vaginal wash they were 128 and 8, respectively. Control mice immunized intranasally (i.n.) with EB had IgG titers in serum and the vaginal wash of 48,600 and 80, respectively, while the IgA titers were 5,400 and 320, respectively.
Determination of the different chlamydial-specific IgG subclasses in serum showed that the mice immunized with vortexed MOMP had an IgG2a/IgG1 ratio of 2 (25,600/12,800) (Table 1), while the mice immunized with the sonicated MOMP had a ratio of 0.2 (26,700/145,000). Animals inoculated i.n. with EB had a predominant Th1 response with an IgG2a/IgG1 ratio of 9 (48,600/5,400). The control mice immunized with ovalbumin had no detectable levels of chlamydial-specific antibodies.
No significant differences in the neutralizing antibody titer were observed between the groups inoculated with MOMP or EB. The neutralizing antibody titer in the serum from the mice inoculated with the vortexed and sonicated MOMPs were 810 and 1,350, respectively, while animals immunized with EB had a neutralizing titer of 1,350 (Table 1).
Serum samples were also tested for the presence of specific antibodies to octameric peptides of the MOMP. As shown in Fig.3, IgG2a and IgG1 antibodies to the four VD of the C. trachomatis MoPn MOMP were detected in the animals inoculated with both MOMP preparations. However, mice immunized with the sonicated MOMP had, overall, a weaker IgG2a than IgG1 response to the VD than the animals immunized with the vortexed MOMP. As previously shown, mice inoculated with EB had IgG2a but no IgG1 antibodies to the VD (18, 21, and data not shown).
A significant EB-specific T-cell proliferative response, as measured by a lymphoproliferative assay, was detected in the mice immunized with the C. trachomatis MoPn vortexed MOMP and in those inoculated i.n. with EB, while animals immunized with the sonicated MOMP had no significant T-cell response (Table2). In vitro cytokine production by splenocytes showed a predominance of IFN-γ over IL-4 levels in the mice immunized with the vortexed MOMP and in those inoculated i.n. with EB, while animals immunized with sonicated MOMP had background levels of both IFN-γ and IL-4 (Table 2).
Vaginal shedding of C. trachomatis following the intrabursal challenge.As shown in Table3, 25 of the 28 (89.9%) control animals inoculated with ovalbumin shed C. trachomatis over the 6 weeks of the experiment. In contrast, only 7 of the 29 (24.1%) mice immunized with the vortexed MOMP had positive cultures during that period of time (P < 0.05). The duration and intensity of the shedding were also significantly different between these two sets of mice (Table 3). On average, the number of IFU recovered was 1 log10 lower in the animals immunized with vortexed MOMP than in those inoculated with ovalbumin. A more limited protection was observed in the group of mice immunized with the sonicated MOMP. Of the 25 mice, 16 (64%) had positive cultures, and only during the first week was there a statistically significant difference in the number of IFU recovered from the mice immunized with the sonicated MOMP versus that recovered from ovalbumin. As expected, almost complete protection was obtained in the group inoculated i.n. with EB. Of the 18 mice in this group, only 1 (5.6%) had a positive culture on the second week, with a very low level of C. trachomatis MoPn IFU detected.
Fertility studies.Table 4shows the results of the fertility studies. In the ovalbumin control group, only 3 of the 28 (10.7%) mice had embryos in both uterine horns. In contrast, of the mice immunized with vortexed MOMP, 16 of the 29 (55.2%) had embryos in both uterine horns (P < 0.05). However, animals immunized with the sonicated MOMP did not have a statistically significant increase in fertility. The group inoculated i.n. with EB and the fertility control group also had higher fertility rates than the ovalbumin control (P < 0.05). Furthermore, mice inoculated with ovalbumin or sonicated MOMP had significantly fewer embryos in the challenged left uterine horn than the fertility control animals (P < 0.05). In contrast, no significant differences were observed between the number of embryos in the right and left uterine horn in the animals immunized with vortexed MOMP, or in those inoculated i.n. with EB, compared with the number of embryos in the fertility control group.
In this report we have shown that immunization with a preparation of the C. trachomatis MOMP, extracted directly from the organism, can induce significant protection against a genital challenge. This is, to our knowledge, the first time that a highly purified antigen of C. trachomatis has provided protection against a genital infection and infertility. This parallels the encouraging results recently reported using an anti-idiotypic antibody to the exoglycolipid antigen of C. trachomatisto protect mice against an ocular challenge (57) and the positive data obtained with DNA plasmids coding for the MOMP against an intranasal challenge (58).
Of the several antigens present in the chlamydial outer membrane, the MOMP appears to be the most obvious candidate for a vaccine against chlamydial genital infections (10, 41, 53). Based on that premise, various groups have used preparations of the MOMP, peptides corresponding to the VD, or DNA plasmids coding for the MOMP as an antigen in an attempt to induce protection (26, 31, 36, 44, 48,49). Unfortunately, the results have been disappointing. Several explanations could account for these negative results, including the route of delivery, dose of antigen, and adjuvant preparations. On the other hand, a factor that has been considered by several investigators as potentially critical in inducing a protective immune response is the structural conformation of the epitopes of the MOMP (26, 36,44, 49). In this respect, we have shown that a purified preparation of the chlamydial outer membrane complex, consisting mainly of the MOMP, the 60-kDa cysteine-rich protein, and LPS, can induce protective immunity against a genital challenge (31). Similar results have also been reported using a preparation of the outer membrane to protect sheep and guinea pigs against Chlamydia psittaci (2, 47). It was, in part, on the basis of these results that we considered the need to refold the MOMP before vaccination in an attempt to reconstitute the protective epitopes present in the native outer membrane of C. trachomatis. Here, our data suggest that epitopes that are formed by refolding the MOMP may be critical for inducing a protective immune response. Refolding may reconstitute some of the nonlinear protective epitopes present in a single MOMP molecule in the native EB and also those formed by homopolymers of MOMP (23). The fact that sonication of the folded MOMP resulted in a decrease in its protective ability supports this interpretation, although an alteration of linear epitopes by sonication cannot completely be excluded. This conclusion is also upheld by the finding that a MOMP preparation extracted and purified in the same manner as that reported here but not refolded failed to induce protection (31). Obviously, until the crystal structure of the MOMP and its conformation in the EB are elucidated, no definitive conclusions can be reached.
That a specific conformation of the epitopes appears to be important for inducing a protective response suggests that the humoral immunity plays a substantial role in this animal model (6,22). This supports the observation originally described with vaccines against trachoma in humans and monkeys, indicating that the protection was serovar specific (13). It is important, however, to consider that the development of protective CD4+ T-cell responses may also depend on the proper conformation of the inducing epitopes. For example, Sjolander et al. (40) have shown that the native surface antigen 2 from Leishmania major can induce a protective response, while the same antigen produced in Escherichia coli failed to elicit protection. Since protection in mice againstL. major is dependent on T helper cells, the authors concluded that correct protein folding and/or posttranslation modification maybe needed for eliciting a protective CD4+ T-cell response.
Other than the innate immune factors and the natural anatomical barriers present in the genital tract, protection against infection, called sterilizing immunity, will have to be mediated by antibodies on the mucosal surface (41, 53). A protective role for local antibodies in humans was first suggested by Brunham et al. (3), who showed an inverse correlation between the titer of IgA in genital secretions and the quantity of infectious units ofC. trachomatis isolated from the cervix. Experimental proof that a monoclonal IgA antibody to a conformational epitope of MOMP could neutralize in vitro the infectivity of C. trachomatis MoPn has been reported (30). Subsequently it was demonstrated that passive immunization with this IgA antibody resulted in a significant decrease in the number of mice infected and in the intensity and duration of vaginal shedding following an intravaginal challenge (32).
Although IgA antibodies can block an infection at the site of entry, the challenge will be to develop a vaccination protocol that induces and maintains a high level of antibodies in the genital mucosa. Thus, in addition to inducing protective antibodies a vaccine most likely will also have to induce cell-mediated immunity. In this respect it appears that, at least based on experimental data with mice, a predominant Th1 response will be more efficient at eradicating a chlamydial infection than a dominant Th2 response (15, 21,37). In general, immunization with viable organisms, includingC. trachomatis, induces a predominant Th1 response, while nonviable antigens tend to elicit a Th2 dominant response (4, 18, 27, 31, 58). The vortexed MOMP preparation used here elicited a predominant Th1 response, while the sonicated MOMP induced mainly a Th2 response, as shown by the IgG2a/IgG1 ratio and the levels of IFN-γ and IL-4 produced by the splenocytes. These findings, in addition to the stronger T-cell proliferative response elicited by EB in mice immunized with the vortexed MOMP, suggest that the epitopes of this preparation more closely resemble those present in the native EB than those in the immunogenic sites of the sonicated MOMP.
There are presently several mouse models to test vaccine protocols and analyze the pathogenesis of a genital chlamydial infection (1, 9,51). Each one of them has unique advantages, but not without shortcomings. The model of intrabursal inoculation used here was originally described by Barron et al. (1) and offers the advantage that all strains of mice so far tested, independent of age, develop infertility following a relatively low challenge with theC. trachomatis MoPn serovar (18). The obvious shortcoming of this model is the unnatural route of inoculation. The model in which the mice are challenged intravaginally requires a large dose of C. trachomatis MoPn, and certain strains of mice appear to be completely resistant to the development of infertility if they are inoculated past a certain age (9, 29). To overcome this limitation, an alternative model was developed in which the mice are treated with progesterone before they are challenged with Chlamydia (51). Treatment with progesterone, however, not only makes the genital epithelium more susceptible to a chlamydial infection but also induces a significant alteration of the immune system (14, 17,35). This, in our opinion, may be a significant shortcoming when testing a vaccine candidate, since treatment with progesterone may abrogate the protective immune response induced by the antigen. Thus, presently we do not have an ideal animal model to test vaccine candidates against chlamydial genital infections. We think, however, that if different groups of investigators test their vaccine candidates in several murine models, it is likely that, based on their accumulated experiences, conclusions could be reached that are applicable to a large segment of the human population by the time that a vaccine candidate is ready for clinical trials.
Several steps will have to be explored before we can implement a vaccination protocol in humans with a MOMP preparation. The most obvious is the need to obtain quantities of MOMP sufficient for vaccination. Although it is possible to increase the production of MOMP using tissue culture techniques, this issue can probably be better addressed by exploring some of the recombinant techniques now available. However, this will not be an easy task, since it will require not only the production of the MOMP but also the purification and refolding of the protein into the proper conformation. Structural characterization of the MOMP preparation that we have described, including its crystallization, could be very helpful to start addressing this problem. The use of MOMP will still pose another question, and that is the still-unresolved issue of whether or not this protein from one serovar can protect against all the otherC. trachomatis serovars (34, 49). This will have to be addressed in the murine and monkey models before clinical trials are performed with humans (1, 9, 33, 51).
In addition, the issue as to whether or not the trace amounts of LPS present in this MOMP preparation may directly or indirectly play a role in protection will probably not be answered until a recombinant vaccine is tested. The fact that a nonrefolded preparation of MOMP that was extracted and purified using the same procedure utilized here did not induce protection suggests that if the LPS plays a role, it most likely will do so indirectly by modifying the MOMP (31). Alternatives to the use of Freund's adjuvant will also have to be explored. Various adjuvants are under intense investigation for other vaccines, so knowledge gained with other antigens may be applicable to the MOMP (7). In conclusion, we have shown that a purified and refolded preparation of the MOMP can induce protection against a genital challenge with C. trachomatis in a mouse model. A significant amount of work, however, is required before we can consider applying this approach to humans.
This work was supported by Public Health Service grants AI-32248 and AI-30499 from the National Institute of Allergy and Infectious Diseases.
Editor: A. D. O'Brien
- Received 29 March 2001.
- Returned for modification 7 June 2001.
- Accepted 19 July 2001.
- Copyright © 2001 American Society for Microbiology


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This chocolate box, traditional village is one of Austria's most exclusive resorts. Lech is a picturesque town surrounded by stunning mountain peaks with a flowing river paving its way through this beautiful town to the lovely 14th century church. Lech is a fantastic resort for intermediate skiers with easily accessible slopes and famous white ring circuit that links Lech and Zurs as well as beautiful scenic runs linking the resort Overlech. For more advanced skiers there are numerous deep snow runs, plenty of off piste opportunities and Lech is one of the only Skiing resorts in Austria to offer Heli-skiing. The Alberg ski pass covers neighbouring resorts Stuben, St Christoph, St Anton and Sonnenkopf giving you plenty of opportunity to explore all of Austria's incredible skiing at all levels.
Lech is known for its sophisticated style of après ski, with champagne bars and exclusive boutiques, it is a highly exclusive resort that has a selection of luxurious hotels and restaurants as well as lively local bars. This is a great place for reunion with friends or a romantic getaway with horse draw sledges taking you through the magically romantic Zug Valley.
Austria is home to some of the top Luxury Ski Chalets offering large and spacious Chalets equipped for 10+ people. Only a small amount of Luxury Ski Chalets can be viewed via our website for your own presentation of properties please contact our specialist Ski Consultants today.


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Tulip Group has been successfully delivering its projects year after year where clients are cherishing their stay. This has been the main goal of Tulip Group and this organisation fulfils its commitments always. This is the key to success of Tulip Group and the main reason for the enviable
position of Tulip Group where
it stands today in the Real Estate
In all Tulip projects, special attention is given to the Elevations of the building besides being functional in the best possible way. The beautiful elevations of these towers give a traditional with modern look enhancing the aesthetics, ambience, aura and serenity all around. (In Photo : Tulip Violet Club)
Here at Tulip, we believe in solving problems instantly rather than waiting for them to pile up. Our hard working team is dedicated to find solutions in every way possible, so we can deliver you the best home.
Tulip Group is a Real Estate Development Organisation based in Delhi-NCR in India, with its Corporate office in Gurgaon and registered office on Barakhamba Road, Connaught Place, in the heart of New Delhi. Tulip
was started by Mr Parveen Jain (CMD) Chairman and Managing Director, in the year 2005 , a first generation entrepreneur having more than 30 years of experience in construction, real estate and development. His vision, dedication, hard work, objective approach and leadership qualities changed the future of Tulip Infratech Pvt. Ltd to make it an ISO 9001-2000 company.
Tulip Group is a company which has achieved excellence through its foresightedness and expertise in its field. The focused vision, undivided dedication and constant efforts of the company help it to develop strategies for its ceaseless growth in the sphere of real estate and construction.
Maintaining the highest standards of quality has always been the foremost priority at Tulip, enabling it to earn an enviable reputation in a brief period of time. With residential and commercial projects, planned to create a benchmark in the future, Tulip is embarking very fast on the way to success.
For any inquiries, questions or commendations, please call: +91 124 441 7777 or fill out the following form
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Apple CEO Visits China, Focuses on App Developers amidst Dropping iPhone Sales in the Area
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China has always been a difficult cookie to crack. Incredibly independent, the Chinese economy has been one of the fastest in terms of growth and development within the past year. International corporations and businesses have been eyeing China for a while, longing to establish a relationship with the superpower. Not only has China grown in power politically, but its technological innovations are no laughing matter as well. China was able to suppress and lower the sales of multiple international tech companies by creating their own local versions. Because of this, many corporations seek to establish relations with China in order to gain the support of the Chinese tech community.
Apple CEO Tim Cook visited China for a Forum on March 23. He was seen touring app developers that specialized in Augmented Reality, an innovation that Apple has been taking by storm since the release of the iPhone X. However, Cook was criticized for not addressing the lack of consumer interest within China for Apple's products. Instead, Cook prioritized looking for corporations to contact with for further innovation of the iPhone.
Big fish here, small fish overseas
China has been known as the home for cheaper alternatives to high-end tech products overseas. Corporations have been known to mimic Apple's style and form while choosing to use cheaper, sometimes sub-optimal parts in order to create something similar to the Apple experience. Companies like Xiaomi and Oppo have been successful at winning the hearts of Chinese consumers with their functional yet affordable alternatives to Apple's more expensive products.
Cook constantly has trips to China to maintain ties with investors and look for corporations to contract and become producers of Apple product parts. However, this closely watched trip saw cook trying to expand Apple's global footprint by improving on the Augmented Reality that the new iPhone series specializes in. People believe that Cook going to China for expansion proves Apple's interest in getting the people of China to be interested in their products.
Gaining intel
Some individuals believe that Cook's trip to China was more than just expanding Apple's capabilities, but also an opportunity to gauge the competition within China. Since the Chinese public prefers the cheaper alternatives, gathering intelligence regarding the needs of Chinese consumers can help Apple get a leg up on their Chinese competition. Moreover, it grants Apple visibility as a corporation that actually cares about the needs of its consumers. iPhone sales are still suffering from stiff competition from Chinese domestic brands and overall declines in smartphone sales in China. If Apple pushes its digital products and other services in the Chinese market, there might still be hope for the tech giant in the Chinese market.
Apple recognizes how vital it is for them to capture the Chinese market. They're not the only ones suffering because of Chinese preference, with main competitors Samsung and Google suffering in the sale of their flagship smartphones within China a well. If Apple is capable of capturing the Chinese market, it gives them a huge boost in sales and reach that might be difficult for Samsung and Google to catch up with, putting Apple in a secure spot at the top of the tech hierarchy.
Tim Cook's trip to China caused millions to wonder what the next step of the tech giant would be. By ignoring the dropping sales in China, Cook may have set up the demise of the iPhone within the Chinese market. However, if he was able to gather information and data regarding the Chinese demographic and would be able to channel that into innovation, then he might be able to save Apple's reputation within China and retain its spot as the top tech corporation in the world.


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At some point practically everyone dreams of receiving a financial windfall. It may come in the form of a lottery win or the sale of an unexpectedly valuable item. Others may dream that somewhere in the world they have a long-lost relative who has identified them as the individual who should inherit their substantial end-of-life estate.
While many Californians do receive inheritances from their relatives and other loved ones, in most cases those items bestowed upon them are sentimentally valuable rather than financially gratuitous. From time to time, though, a person may receive a sizable inheritance that has the power to alter their financial future.
In order to prevent an individual's inheritance from becoming a marital asset subject to property division during a divorce, several conditions must be in place. First, the bequest must be made to one person only, as any bequest that is given to an individual and their spouse is considered theirs jointly and therefore subject to division.
Second, the individual who receives the bequest should not mingle assets from the inheritance in accounts that are co-owned with their significant other. As readers of this family law blog may know, comingling separate assets with marital assets can convert all or part of the separate assets to marital assets when it comes time to divide up a couple's shared property.
Finally, the individual recipient of an inheritance must maintain their inheritance in a separate account and apart from their spouse. If this money is used for marital living expenses, there is no right for these funds to be reimbursed. If inherited money is used to purchase a jointly-titled asset, such as using the funds for a down payment on a home, the amount that can be proven to have been invested from inherited funds may be reimbursed to the contributor. However, this reimbursement is without interest and without a share of any appreciation in the value of the asset.
An inheritance should be treated with care to prevent it from losing its separate status. With the right information, a person can make good choices regarding how maintain the separate character of their inheritance.


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Free childcare scheme closes its education, reports charity
Charity reports that a scheme that used to provide 30 hours a week of free childcare had faced a financial crisis on providers.
Since last years' September, most parents in England were offered with free care for their children aged 3-4 years during term time. However, PSLA (Pre-School Learning Alliance) reports that most childcare providers are struggling hard to remain open due to the increase in running costs.
The government said that it would try to "continue to monitor delivery costs".
According to the Education Department, parents over 340,000 three-four years old have taken advantage of the scheme since it commenced, over a year. Between July 17 and August 23, PSLA charity has surveyed 8000 childminder firms and nurseries.
The survey obtained answers from 1662 providers and discovered that over 46% felt that the free childcare scheme "had a negative financial impact on their business", whereas, 2/3rd said that funding for child care did not "cover the full hourly cost of delivering the places."
Managing Director of The Acorns, Gillian Simpson-Morris in Eldwick day nursery, said that she felt squeezed as child care funding has dropped by 66% to £4.10 an hour, which cost of everything is much high.
She further said that "we have to pass the cost on to parents – we've nowhere else to go with it."
"Because of price hikes everywhere else, everything we buy is going up, the salaries are going up, we've got living wages going up, minimum wages going up, it's not a very highly paid sector but we try and pay what we can," she added.
Morris continued that "we have to be viable. If we're not viable then we would disappear and lots of providers nationally have disappeared."
Two children's mother Jennifer McCanna from Sheffield said that despite the scheme was not 'completely free'. Therefore, she saved £400 a month.
Mrs. McCanna continued that "I completely see the point of view of the childcare providers because they have to make their business work."
Neil Leitch, Chief Executive of PSLA claims that the free childcare scheme required adequate funding.
She further said that "It's a great thing for the parents. It is not a great thing for the industry. In fact, we're seeing nurseries close specifically because of the introduction of this 30 hours policy."
"For the thing to be a success it," she added.
In a statement, the Education Department said that it offers "£1bn extra funding a year to deliver all of this government's free childcare offers."
It continued that "We continue to monitor delivery costs and we have commissioned new research to provide further information on the costs around childcare."
Education Department also said that parents in England saved up to £5,000 per year on their children care costs.


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Here's how to become a Mac power user. All you need is the right set of apps. And an attitude (think, 'holier than thou').
One of those apps that will improve your productivity, enhance your geek, and bring shock and awe to the faces of your neighbors as they watch you do more with less effort on your Mac is Butler. The idea behind Butler is simple. Make things you do frequently happen faster. It's all about Triggers and Tasks.
Butler, as it is with many Mac utilities, lives in the Mac's Menubar, a mere click away.
Before using Butler you'll need to setup and configure the Triggers and Tasks. Triggers are Hot Corners, Events, Hotkeys, Menubar, Abbreviations, and Popup Menus.
Tasks can be assigned to each and include Launch Apps, Open Files, Open Preferences, Manage Bookmarks, Run AppleScripts, Simulate Keystrokes, and many, many more.
Once you've walked through the setup, Butler awaits your command. Select one of the Triggers and an action and– poof!– you're a Mac power user.
While Butler is definitely an app that gets you into the level reserved for Mac users who like power, you'll need to walk through each of the configuration options (Triggers to Actions) to make it work.
Butler is pretty good, will certainly improve your productivity, but also increase your credit card balance more than expected.