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Methods and Meaning - ForumTask: Post an image to the forum that you think is an example of a good use of a photographic 'faux pas' or what we might traditionally think of as a 'mistake'. This might be a 'happy accident' or it could be when someone has deliberately subverted, or broken, the technical rules of photography. It could be one of your own images or a picture taken by someone else. My response: This photo was taken on a 1954 Voigtlander Vitessa (http://camera-wiki.org/wiki/Vitessa). It has an unusual film winder mechanism in the form of a large plunger rod. For some reason on my camera the film does not always wind on, resulting in the occasional double exposure. I do like the randomness of not knowing when this will occur and the resulting 'happy accident'. This particular shot was taken at Fort la Latte in Brittany where I was on a high vantage point on the fort and so took a photograph of part of the fort and another of the surrounding scenery. The combined double exposure has blended these 2 shots giving a surrealist feeling to the resulting outcome and also created a layering effect to the background, giving a further sense of depth to the image. These were the responses from other students: I like the multiple horizon lines almost looking like hills in the background behind the castle. Works in B&W but I don't think it would work in colour. Oh yes... a double exposure is a great example of a happy accident.. I had to think quite hard to get my head around what a 'happy accident' or faux pas would even look like. Thank you for opening my mind!! This really is a happy accident. I've had often had similar issues with my analog cameras and the accidental exposures have a special place in my heart. The unexpected and unintentional beauty is often the powerful. METHODS and MEANING: Activity and WebinarTask: Write a short entry (c.150 words) to the forum below explaining, in your own words, how their methodologies contribute to how you interpret the work. Please insert an image or a hyperlink to examples of the work with your entry. My response: Brassai's was inspired by the work of Eugene Atget, although whereas Atget's is best known for capturing the disappearing architecture of 'Old Paris', Brassai was more intent on capturing the Parisian nightlife, especially the 'shadier' side of nightclubs, bars and brothels. Brassai's methodology derived from his training as a painter and sculptor. Brassai framed his shots so that small areas of light pierced large areas of blacks and shadows. Light reflected in wet streets and diffused by fog, would define shapes within the dark. This contrast gave his printed images richness and depth. In order to light the darker areas of Paris at nighttime, Brassai was equipped with a Voigtlander 6.5x9cm camera, a slow lens and a wooden tripod. He used harsh, direct lighting with long exposures, which were often given an excessive contrast from streetlights or car headlamps. This resulted in a cinematic quality to his images with a film noir feel to them that I find distinctive about his work. METHODS and MEANING: ReflectionReflect:
Consider also the points raised in the presentation:
We were asked to post the following on the forum last week: Post an image to this forum by way of an introduction to your peers and your tutors. Try and respond to ideas and examples discussed in the presentation. You could use a mirror quite literally, or think about views into your personal world that reveal something about yourself or your interests in photography. Include one or two lines about your concept and/or visual strategy. This was my response: I have chosen to use this 'selfie' for as I feel this both introduces myself and acts as an analogy for 'Mirrors and Windows'. This image was taken at the Goodwood Revival on Friday which is a celebration of bygone days, vintage fashion and motor racing around around the classic circuit from the 1948-1966 era. It was part of a series I was taking as a window on the event itself, to try to capture the mood, atmosphere and context. I was using an Olympus Pen-F which is a retro camera based on the original 1960's Olympus film camera of the same name, but to get more of an authentic feeling to the images I used a vintage Asahi Takumar lens. This is shown in the reflection in the mirror which I feel also gives an insight into my interest in the evolution and history of photography.
Here are a couple of responses, one from one of the tutors and another from a fellow student: 'I love that the camera (or the lens) has become the mark of the nostalgia of the even and that's reflected in the image itself and its out of focus swirls of red (Saul Leiter again).' 'The camera and lens immediately captured my attention... Your story about the image and the event has me wanting to see the entire series! There is a great reverence shown--photographing a vintage event with vintage gear... Profound. Thank you for sharing!' Topic 1: MIRRORS and WINDOWS: Reflection What do you make of the 'mirror' and 'window' analogy? How helpful is this in understanding the nature of photography? I think that the 'mirror and 'window' analogy really helps to break photography down to a very basic level, as it could be said that all photographers are showing you a window of the world as they see it and also mirroring their own vision, mood or feeling in the context of how they choose to show this. Photographers such as Niépce, Fox Talbot and Daguerre showed the use of windows both physically and metaphorically from the very beginnings of photography. Mirrors have also been widely used in photography in the physical sense from the first ever 'selfie' by Grand Duchess Anastasia Nikolaevna in 1913 to Brassai, through Brassai's image 'Couple Souriant, Balmusette des Quatre Saisons, Rue de Lappe, 1933' to Elliot Erwitt's California kiss, 1955. The metaphorical mirror is not always as easy to highlight through a photographer's work, although the clues are often there for you to interpret and get an insight into the photographer themselves. Robert Adams described landscape photography as being a mirror of what goes on inside you. In Beauty and Photography, Adams writes of '…something in the picture that tells us as much about who is behind the camera as about what is in front of it' (Adams, 1996, p. 15.). Don McCullin's landscapes are often dark, haunting vistas that reflect his inner turmoil after years as a war photographer. As an image maker, do you identify more closely with one or the other? My own images tend to both show a window of my world and how I want my viewer to see it and I do like to use different photographic equipment and techniques to achieve the effect I am trying to get across in my work. I believe by doing this I am reflecting my own personality into my images. I have been inspired by a lot of photographers and I think I draw on this when taking my photographs and think this is also reflected in my work. What other metaphors do you know of, or can think of, that provide an insight into photography? Another metaphor which you often hear associated with photography is 'Eyes are the window to the soul'. This is certainly true in the iconic Steve McCurry image, 'Afghan Girl'. In portrait photography it's the eyes more than any other part of the image which draw us in and make us feel connected to the person. What is your motivation for photography? What do you want to learn about and how can photography help you get a greater understanding of it?
My motivation derived from working in a professional photographic laboratory after leaving college. I loved the whole process of creating photographs which made me realise that the camera is just part of the image making process. Through teaching photography I have myself learnt a lot more about the history and evolution of photography and I am fascinated with both historical processes and the latest technology and how photography is continuing to evolve. Photographers are often using their images to highlight environmental issues such as global warming, but I am interested in looking at the environmental impact of photography itself with both the current digital technologies and historically through analogue photography and processes. I would like to explore the most eco-friendly approach to taking images using both current and past technologies. |


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COALINDIA (NSE) is expected to give a bullish movement in the September expiry. Buy one lot of COALINDIA 185 call option at 7 with a strict stop loss at around 180 for the scrip. Hold the position till the scrip achieves the target of 195.
Place bid for buying COALINDIA 185CE @ 7.00

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The Indian Farmers Have Been Protesting Against The New Farm Laws That Were Passed In The Lok Sabha On 17th Of September 2020 And 20th September 2020 In Rajya Sabha. Since Then A Huge Protest Has Been Going On In The Opposition Of The Three Farm Bills And The Only Demand Of The Protesters Is To Repeal The Bill.
On 26th Of November 2020 The Protesters Called A 24 Hour All India Strike, While Marching Towards The Delhi Borders, On 26th Of January 2021 The Peaceful Protest Took A Violent Turn And Many Innocent Lost Their Lives. As A Result Of Which The Government Banned The Internet Around The Area And Baricatted The City. After The Violation Of Peace And Many Human Rights, Some International Personalities Came To Support The Farmers On Twitter, Starting A Twitter War. On The Other Hand, Delhi Police Lodged An Fir Against The Swedish Environmental Activist Greta Thunberg Who Recently Uploaded A Toolkit On Her Twitter Account Prescribing The Actions That Can Be Taken To Show Support To The Farmers.
The All India Congress's General Secretary Mrs. Priyanka Gandhi Wadra Came Forward To Show Their Party's Support To The Protesters And Opposition To The Laws. On 15th Of February, She Held A Kisan Panchayat In Bijnor, And Will Hold Two Other Panchayats On 19th & 20th Of February 2021, In Mathura And Muzaffarnagar Respectively. The Leader Has Already Attended A Kisan Mahapanchayat On 10th In Saharanpur.
The General Secretary Condemned The Farm Bills Claiming That They Were Soley Formed And Constructed To Favour The Billionaires Of The Country. She Called Out On The Government Saying That The New Farm Laws Will Lead To The Monopolization Of The Agriculture And The Farmers Will Be Exploited By These Big Franchises. She Condemned The Allegations That Were Made Against The Protesters By The Ministers Of The Ruling Party And Said That The Government Had Looked Down Upon The Farmers And Have Undermined Their Dignity By Calling Them, Terrorists And Traitors.
The All India Congress Was Strictly Against The Bill And Is Now Demanding The Government To Repeal The Laws. Mrs. Wadra Condemned The Ministers Of The Cabinet And The Ruling Party For Their Statements Against The Farmers.
The Leader Gave A Speech Condemning The Acts Of The Prime Minister, She Said That Acts Of Negligence And Ignorance On The Part Of The Government Are Sevre Mistakes That Are Being Done. As Per Her Speech A True Leader Works For His People, With His People.
The Former Party Chief Mr. Rahul Gandhi Has Repeatedly Come Forward To Show His Support To The Protesters, Meeting Them And Saying Words Of Affirmation To Them. He Is Also Against The Laws And Has Demanded That The Government Should Repeal Them.
The Upcoming Panchayats Are To Be Held By The General Secretary Where She Will Be Referring To The Farming And Showing Her And The Party's Support For Them. She Will Also Visit The Families Who Lost Their Members As A Result Of The Violence That Took Place On The Republic Day.


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Bone spurs are areas of smooth, excess bone that can develop as you age. Cedars-Sinai says they are most common and noticeable in adults over the age of 60. Bone spurs can develop anywhere in your body from:
- natural wear and tear on your bones and joints
- underlying medical conditions
- Injuries
While bone spurs alone aren't usually painful, these growths in your neck can become symptomatic as they press on nerve endings in your spine and cause pain or discomfort when you move your neck.
According to Cedars-Sinai, it is estimated that around 40 percent of people with bone spurs need treatment for their symptoms. Learn about the symptoms and causes of bone spurs in the neck and what to do about them if your symptoms are extremely painful and interfere with your daily activities.
Bone spurs in the neck cannot cause symptoms at first. But if the bone spurs get bigger, you may notice:
- swelling
- tenderness
- a visible lump that you can feel to the touch
As bone spurs progress, they can cause more serious symptoms that can affect your quality of life.
You should see a doctor if you have the following symptoms:
- chronic dull pain
- Pain radiating from the neck to the head
- headache
- Numbness or tingling sensation that can spread to your arms and hands
- Muscle spasms that may radiate into the shoulders
- Stiffness and restricted range of motion (e.g., turning the neck from side to side)
If a bone spur is suspected in the neck, a doctor will likely recommend imaging tests such as x-rays. This can help confirm any areas of excessive bone growth along your cervical spine.
Here are some examples of what x-rays of bone spurs in your neck can look like.
Bone spurs have many causes. A 2017 research report showed that they are more common the older you get.
Depending on where they are in your body, lifestyle can be a factor. Bone spurs on the feet can be caused, for example, by impact-intensive exercises or being overweight.
Specific risk factors for bone spurs in the neck can include:
- History of Sports Injuries
- Car accidents or other incidents that cause whiplash
- Overuse injuries, especially from desk jobs
- Inheritance
- Ankylosing spondylitis
- diffuse idiopathic skeletal hyperostosis (DISH) spine
It is important to note that stress from persistent racism, discrimination, and other racist systems can play a role in the development of the disease beyond genetic factors.
A 2020 animal study showed that bone spurs are also common in osteoarthritis (OA). This type of arthritis is common as we age and can cause the joints to collapse over time.
OA can affect your neck directly, but it is also possible that your vertebrae are affected in other parts of your spine. When pressure is placed on your spine, bone spurs can grow between the vertebrae, causing neck pain.
Arthritis of the neck is also known as cervical spondylitis. The American Academy of Orthopedic Surgeons says about 85 percent of adults ages 60 and over develop this condition. When the joints wear out, bone spurs can develop.
The American College of Rheumatology says other common causes of neck pain in general are conditions that affect your spine, such as a herniated disc or spinal stenosis. These can lead to bone spurs, but this type of complication isn't as common in the neck. Neck bone spurs can also occur with cervical stenosis (neck).
To diagnose a bone spur in the neck, a doctor will first perform a physical exam. They can ask you questions about your symptoms and test the mobility of your neck. A bone spur on the neck can be confirmed by imaging tests, such as:
- X-rays
- Computed tomography (CT) scans
- Magnetic resonance imaging (MRI)
The tests can also help diagnose underlying causes such as OA.
Your doctor may also recommend an electrical conductivity test to check for nerve injuries in your spinal cord. Blood tests may also be ordered to rule out the possibility of other underlying conditions, such as rheumatoid arthritis.
Treatment for bone spurs will depend on the severity of your symptoms and your overall condition.
Lighter cases can be handled with one or more of the following options:
- rest
- cold compresses for pain relief
- Steroid injections to reduce inflammation and subsequent pain
- Over-the-counter (OTC) or prescription non-steroidal anti-inflammatory drugs (NSAIDs) that are only for temporary use
- Paracetamol (Tylenol) for mild pain
- Physiotherapy to increase freedom of movement (planned up to three times a week for 2 months)
- Massage therapy for pain relief
In more severe cases where symptoms are unresponsive to therapy and medication, a doctor may recommend surgery on the cervical spine (neck).
The type of surgery for cervical bone spurs depends on the underlying cause and location – some examples include:
- Spinal fusion to weld two or more vertebrae back together
- anterior cervical discectomy to remove spurs and discs from the front of the neck
- anterior cervical corpectomy Used to remove and replace vertebrae when bone spurs cannot be removed by discectomy
- posterior cervical laminectomy to remove the lamina in the neck and get rid of bone spurs that can press on the spinal nerves
A doctor will discuss with you all the benefits and risks of surgery to remove the bone spur. The American Association of Neurological Surgeons says that while surgery is rare, it carries the risk of nerve and spinal cord damage, as well as increased pain.
Rest is important with neck pain. But a doctor can refer you to a physical therapist who can guide you through exercises that will help:
- Reduce pain
- Improvement of the freedom of movement in the neck
- Build strength and improve posture
Below are two neck exercises suggested by the North American Spine Society that you might want to discuss with a doctor or therapist.
Neck retractions
In a sitting or standing position, keep your head in a forward facing position while gently pressing your fingers against your chin. You should feel a stretch in your neck.
Hold this position for up to 2 seconds, up to 10 times in a row. The North American Spine Society says you can repeat these retractions up to four times a day.
Correct posture
Your physical therapist will also help you maintain correct posture to improve your symptoms. Try this all day by following these tips:
- Orient your ears just above your shoulders.
- Create space behind your neck without shrugging your shoulders.
- Roll your shoulders back.
- Prevent your head and chin from falling forward.
Bone spurs in the neck are not painful in and of themselves. But these bone growths can put pressure on nerves over time, causing pain, swelling, and restricted mobility.
Talk to a doctor if you have chronic neck pain so they can get an accurate diagnosis and treatment plan. Bone spurs and other related conditions like OA can be diagnosed with a physical exam and imaging tests.
They can help treat bone spurs with a combination of prescribed medications, rest, and neck exercises. Keep track of your treatment plan and see a doctor or physical therapist if your pain doesn't improve.
We understand how important it is to choose a chiropractor that is right for you. It is our belief that educating our patients is a very important part of the success we see in our offices.


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History Of Second Chance
Second Chance started as a concept in 2005 in EOPS – named after the program at City College of San Francisco for formerly incarcerated students. The founders were Maryanne Michaels, Rafael Vazquez, and Rhonda Findling, all in EOPS. It evolved into a support team of staff that supported this population. It then became a student club that started to get off the ground in 2015-16, with Rhonda Findling being the faculty advisor. In Fall 2018, Student Services Vice President Pedro Avila made Second Chance an official Student Services Program, and appointed Rhonda Findling to be the dedicated counselor and coordinator. The program started with about 25-30 students in 2018 and is now at more than 100 students.
Location & Hours
1501 Mendocino Ave
Bertolini Student Center, 2nd Floor
Counseling Department
Santa Rosa, CA 95401
Phone: 707-524-1543
Email: email@example.com
Summer Office/Space Hours:
Monday-Thursday 9:00am-5:00pm
Friday Closed
One on one support and counseling by appointment
Call or email to book
Second Chance Calendar Events


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text:
Bali has cut its COVID-19 quarantine period from five days to three as it reaches the lowest possible COVID-19 alert, the Coordinating Minister for Economic Affairs announced Tuesday.
In a circular issued on Nov. 2, Indonesia's COVID-19 Task Force modified Bali's formerly stringent quarantine policy.
According to the document, the benefit will be granted to all foreign visitors who can produce both a negative coronavirus test and proof of being fully vaccinated.
"The quarantine period is now three days for international travelers who have been vaccinated," said a spokesperson for the country's COVID-19 Task Force.
Another significant change in the previous law is that partially vaccinated travelers are now permitted to travel to Indonesia. They are, however, subject to a 5-day mandatory quarantine.
All travelers still need to submit proof of having booked a room in one of the 35 hotel-quarantine sites as well as purchasing insurance with a minimum coverage of US$100,000, which includes potential COVID-19 expenses.
Caught between a struggling economy and a potential health emergency, Bali is slowly adjusting to the new reality a number of Asian countries are now facing. Learning how to live with COVID-19 as the rest of the world is doing.
Luckily, things are improving on a daily basis. As of Nov. 4, a total of 120,887,847 Indonesians had gotten their first immunization, with about one million new immunized people per day.
So far, Bali has been fully vaccinated 74,805,667 people, making it one of the most immunized areas in the country.
Also this week, the Ministry of Home Affairs amended Instruction No. 53/2021, to lower Bali and Java's alert to Level 1, the best possible for tourists and business owners.
This means that non-essential businesses, such as shopping centers, and certain service-oriented industries, such as public transportation, can operate at full capacity at least until November 15.
Meanwhile, restaurants, bars, and public facilities, such as public parks, are also allowed to operate with 75% capacity.
Also, travelers who are fully vaccinated will simply need to present an antigen test (cheaper) to be allowed to travel from/to Bali to Java.


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Though the House Democrat health care bill blatantly violates President Obama's central campaign tax pledge, Obama has yet to repudiate the bill. The following tax increases will directly hit Americans making less than $250,000 per year:
- a tax on individuals failing to sign up for health care equal to the lesser of 2.5% of adjusted gross income (AGI) or the average individual premium amount. There is no income floor on this, so this would hit any uninsured American of any income
- a tax on employers for not providing a health care plan equal to 8% of payroll. This becomes 0, 4, or 6 percent of payroll as payday totals dip below $400,000 annually. This will even hit the smallest of small businesses, those making profits of less than $250,000
- codification of the "economic substance doctrine," whereby taxpayers would not be able to engage in legal tax avoidance techniques without demonstrating a bona fide business purpose. This would apply not only to large companies and wealthy individuals, but any taxpayer of any income who engages in a legal tax avoidance technique
These are only the tax increases which would fall directly on Americans making less than $250,000. This doesn't account for the other tax increases in the bill on small businesses which will kill jobs and slash wages.
On Monday, two days before the introduction of the bill, Obama said: "I promised that Americans making $250,000 a year or less would not pay more in taxes. These are promises that we're keeping as reform moves forward."
On Wednesday, when asked for a flat answer as to whether Obama supported the surtaxes in the House bill, White House spokesman Robert Gibbs would only say "It's a process that we're watching."


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Back to Journals » International Journal of Chronic Obstructive Pulmonary Disease » Volume 15
Efficacy and Safety of LAMA/LABA Fixed-Dose Combination Therapies in Chronic Obstructive Pulmonary Disease: A Systematic Review of Direct and Indirect Treatment Comparisons
Authors Hurst JR , Gruffydd-Jones K , Biswas M , Guranlioglu D, Jenkins M, Stjepanovic N , Bamrara A
Received 20 February 2020
Accepted for publication 24 May 2020
Published 1 July 2020 Volume 2020:15 Pages 1529—1543
DOI https://doi.org/10.2147/COPD.S230955
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Richard Russell
John R Hurst,1 Kevin Gruffydd-Jones,2 Mousumi Biswas,3 Deniz Guranlioglu,4 Martin Jenkins,4 Neda Stjepanovic,5 Arushi Bamrara6
1UCL Respiratory, University College London, London, UK; 2GP, Box Surgery, Box, Wiltshire, UK; 3AstraZeneca, Gaithersburg, MD, USA; 4AstraZeneca, Cambridge, UK; 5AstraZeneca Gothenburg, Mölndal, Sweden; 6Parexel International, Punjab, India
Correspondence: John R Hurst Email [email protected]
Background: This literature review assessed comparative efficacy and safety of long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) fixed-dose combinations (FDCs) in patients with COPD and moderate-to-very severe airflow limitation, using evidence from direct (head-to-head) and indirect treatment comparisons.
Methods: Two systematic literature reviews were conducted to identify direct comparisons (head-to-head randomized controlled trials [RCTs]) and indirect comparisons (network meta-analyses [NMAs]; indirect treatment comparisons; meta-analyses) in patients with COPD with moderate-to-very severe airflow limitation. Study/Analysis characteristics, eligibility criteria, patient characteristics, and overall conclusions were extracted from relevant publications. The review of indirect comparisons focused on NMAs reporting efficacy outcomes at 12 and 24 weeks of treatment (established durations of symptomatic studies in COPD recommended by regulators).
Results: Direct comparisons: Four RCTs that provided head-to-head comparisons of LAMA/LABA FDCs were identified, and these varied in their study design, included patient population and reported endpoints. While some differences in lung function outcomes were noted, where assessed, LAMA/LABA FDCs had comparable efficacy in improving symptoms, health status, exacerbations, and comparable safety profiles. However, the differences in study methodology and patient characteristics between these studies made it difficult to draw generalizable conclusions regarding the comparative effectiveness of LAMA/LABA FDCs from the direct comparisons alone. Indirect comparisons: Six NMAs were identified that reported indirect comparisons between LAMA/LABA FDCs; five of these were within the pre-defined scope of this review. Although the scope of each NMA varied, all five concluded that LAMA/LABA FDCs were generally comparable in terms of lung function improvements, patient-reported outcomes, and safety (where assessed).
Conclusion: Although there were some inconsistencies between the outcomes of RCTs and NMAs for lung function, the totality of lung function, symptoms, exacerbations, and safety data suggests that currently available LAMA/LABA FDCs have comparable efficacy and safety in patients with COPD and moderate-to-very severe airflow limitation.
Keywords: chronic obstructive pulmonary disease, direct evidence, indirect treatment comparisons, LAMA/LABA, efficacy, safety
Plain Language Summary
Bronchodilators are medicines given to patients with COPD to help them breathe more easily. Combining two bronchodilators in one inhaler (known as a long-acting muscarinic antagonist/long-acting β2-agonist fixed-dose combination [LAMA/LABA FDC]) may be given to treat symptoms and stop flare-ups ('exacerbations') of COPD. Head-to-head clinical trials are the best way to compare two different drugs. However, there are not many head-to-head trials that have compared different LAMA/LABA FDCs. A network meta-analysis (NMA) is another way to compare two or more different drugs when head-to-head trials have not been done.
In this study, we looked for head-to-head trials and NMAs that compared different LAMA/LABA FDC drugs for people with moderate-to-very severe COPD. We found four head-to-head trials and six NMAs and compared their results.
In both the head-to-head trials and the NMAs, we found that the different LAMA/LABA FDCs were similar for improving symptoms of COPD, quality of life, and stopping flare-ups. They were also as safe to use as each other.
This study showed that, on the whole, different LAMA/LABA FDCs work as well as each other and are as safe as each other.
COPD is characterized by persistent respiratory symptoms and chronic airflow obstruction. It is a leading cause of global mortality and disability,1,2 and by 2030, is predicted to be the third leading cause of death worldwide.3
The Global Initiative for Chronic Obstructive Lung Disease (GOLD 2020) recommends short- or long-acting bronchodilators as initial treatment for patients with COPD, depending on the individual patient's symptom burden and risk of future exacerbations.4 The combination of a long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) may be considered as an initial treatment option for patients with a high symptom burden or for treatment escalation in patients who experience persistent symptoms or exacerbations on monotherapy.4 In the GOLD 2020 report, LAMA/LABA combinations are considered as a class, and no distinctions are made between the available combinations.
LAMA/LABA combination therapy may be delivered via a separate inhaler for each bronchodilator component; however, the use of multiple inhalers can affect adherence and persistence to treatment, compared with the use of a single inhaler.5,6 Therefore, for convenience and to facilitate adherence to medication, several single-inhaler fixed-dose combinations (FDCs) have been developed. LAMA/LABA FDCs currently approved for maintenance treatment of COPD include umeclidinium/vilanterol,7 aclidinium/formoterol fumarate,8 and indacaterol/glycopyrrolate9 (all delivered via dry powder inhaler [DPI]), tiotropium/olodaterol soft mist inhaler (SMI),10 and glycopyrrolate/formoterol fumarate metered dose inhaler.11 The availability of different delivery devices allows treatment options to be matched to patient preferences, characteristics such as inspiratory flow, and device-handling experience.12
For physicians to make informed treatment choices to optimize the management of patients with COPD, it is important to have comparative evidence for the effectiveness of available treatment options.13 However, with the general absence of direct head-to-head comparisons, the use of network meta-analyses (NMA) can provide an indirect approach via a connected network that allows relative treatment effects to be estimated and outcomes across different trials to be assessed.13 As such, a more comprehensive body of evidence is then available by considering both direct and indirect comparisons.14
This literature review aimed to assess the comparative efficacy, in terms of lung function, exacerbations, and patient-reported outcomes (PROs), and safety of LAMA/LABA FDCs in patients with COPD and moderate-to-very severe airflow limitation, using evidence from head-to-head studies and indirect treatment comparisons.
Direct Evidence
A systematic literature review was conducted to identify randomized controlled trials (RCTs) to evaluate direct evidence, which enrolled patients ≥40 years of age with moderate-to-very severe airflow limitation. The systematic literature review was originally conducted with a broader objective and included studies with at least one LAMA/LABA FDC or open LAMA + LABA treatment arm; however, only the studies reporting head-to-head comparisons of LAMA/LABA FDCs were included in the present review. Full details of the search strategy (including search terms) have been published previously.15 Databases evaluated included MEDLINE, MEDLINE In-Process, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). Bibliographic screening of any relevant reviews published in the English language was conducted to validate the searches and ensure the inclusion of all relevant evidence. The databases were searched from their dates of inception to January 2020. Also, databases of abstracts presented between 2016 and January 2020 at the American Thoracic Society, European Respiratory Society, and American College of Chest Physicians annual conferences were hand-searched to retrieve studies not yet published in full-text articles or abstracts reporting supplementary results of previously published studies. Other sources included ClinicalTrials.gov, the International Clinical Trials Registry Platform, the Australian New Zealand Clinical Trials Registry, the GlaxoSmithKline Study Register, and company websites.
A first-stage screening process was conducted to review citations based on the article title and the abstract. Citations not matching the eligibility criteria were excluded at this stage, based on a pre-defined exclusion reason. Also, any duplicate citations were excluded. Two independent reviewers screened all citations, and a third independent reviewer resolved any discrepancies.
Following the completion of the first-stage screening, the full texts of relevant studies were retrieved and examined in more detail to determine a final list of included studies. Two independent reviewers screened the full-text articles, with any discrepancies resolved by a third independent reviewer.
For all relevant studies, details of the study characteristics, eligibility criteria, patient characteristics, and overall conclusions were extracted. To determine the risk of bias for each included RCT, the methodological quality of the study was assessed against a list of criteria relating to randomization and allocation concealment, baseline comparability, blinding, follow-up, selective reporting, and data analysis, including handling of missing data.
Indirect Evidence
A second literature search was performed to identify any indirect evidence. Eligible publications were systematic or targeted literature reviews with any quantitative analysis component, or meta-analyses, indirect treatment comparisons, or NMAs assessing comparative efficacy, safety and/or tolerability of LAMA/LABAs FDCs in patients with COPD with moderate-to-very severe airflow limitation. Only studies with full text in English were included. Analyses that were not based on RCTs were excluded from the review. The full search strategy (including search terms) is presented in the Supplementary Materials (Supplementary Table 1). Biomedical databases including MEDLINE, MEDLINE In-Process, EMBASE, and CENTRAL were reviewed, and bibliographic screening of relevant published reviews was conducted. The databases were searched from their date of inception to January 2020. Also, various Health Technology Assessment databases were searched, including the National Institute for Health and Care Excellence, the Scottish Medicines Consortium, the Canadian Agency for Drugs and Technologies in Health, the Pharmaceutical Benefits Advisory Committee, the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, and Haute Autorité de Santé. Following an initial screen of retrieved citations by a single independent reviewer, a quality assessment of a 20% random sample was performed by a second independent reviewer. A first-stage screening process was conducted as described above for the direct evidence. Full texts of relevant studies were then retrieved to determine whether eligibility criteria of the literature review were met. For the current review, details of the characteristics of the analysis, eligibility criteria, patient characteristics, and overall conclusions were extracted. Also, details of any inconsistency testing conducted to assess whether there was any conflict between direct and indirect evidence were reviewed. The methodological quality (relevance and credibility) of all included indirect analyses was assessed using the International Society for Pharmacoeconomics and Outcomes Research consensus-based 26-item questionnaire.16
Table 1 Study Design and Patient Characteristics of Head-to-Head Comparison Studies |
The final review focused on NMAs that reported efficacy outcomes at 12 and 24 weeks of treatment, established durations of symptomatic studies in COPD recommended by regulators.17
Direct Evidence: Study Characteristics
Using the results of the systematic literature review, four RCTs from three publications were identified that provided head-to-head comparison of LAMA/LABA FDCs in patients with moderate-to-very severe airflow limitation in COPD (Figure 1): the AERISTO study, a 24-week, multicenter, international, Phase IIIb, double-blind study;18 Study A2349 and Study A2350, two identically designed 12-week, multicenter, US, Phase III, double-blind studies;19 and Study GSK204990, an 8-week, multicenter, international, Phase IV, open-label study.20
In terms of the characteristics of the studies identified in the literature search, some differences were noted across the studies in treatment duration, study design (parallel-group vs the crossover), the number of patients randomized, and levels of blinding (Table 1). All four RCTs included umeclidinium/vilanterol DPI as one of the study treatments; this was compared with glycopyrrolate/formoterol fumarate pressurized metered dose inhaler in one study (AERISTO), indacaterol/glycopyrrolate DPI in two studies (Study A2349 and Study A2350), and tiotropium/olodaterol SMI in one study (Study GSK204990).
Differences in inclusion criteria for airflow limitation were noted, with the AERISTO study including patients with moderate-to-very severe airflow obstruction; Study A2349 and Study A2350 including patients with moderate-to-severe airflow obstruction; and Study GSK204990 including only patients with moderate airflow obstruction. The outcomes assessed across the studies also varied. All four studies evaluated changes in lung function as the primary endpoint, although the specific outcomes and timepoints assessed differed across the studies. PROs evaluated included Transition Dyspnea Index (TDI) focal score, COPD Assessment Test (CAT) score, and Evaluating Respiratory Symptoms – COPD (E-RSCOPD) score, although these were not reported consistently across all four studies. None of the studies evaluated quality of life using the St. George's Respiratory Questionnaire (SGRQ). Only the AERISTO study evaluated exacerbations as an efficacy outcome, and only in an exploratory analysis.
Moreover, patient baseline characteristics varied across trials (Table 1). In line with the differences in inclusion criteria, the mean percentage predicted post-bronchodilator forced expiratory volume in 1 second (FEV1) at baseline was highest in Study GSK204990 (59.6%) and lowest in the AERISTO study (48.7%). The proportion of patients with at least one exacerbation in the previous year was almost 2-fold higher in the AERISTO study (47.9%) compared with Study A2350 (26.2%) and Study A2349 (22.1%).
The risk of bias was low in the AERISTO study, Study A2349, and Study A2350, whereas Study GSK204990 was associated with a high risk of bias because of the open-label nature and analysis of the primary efficacy endpoint in the per-protocol population. Also, baseline characteristics were well-balanced across the randomized treatment arms in three studies (AERISTO, Study A2349, and Study A2350), while this information was unclear in Study GSK204990.
Direct Evidence: Lung Function
The co-primary outcomes evaluated in the AERISTO trial were change from baseline in morning pre-dose trough FEV1 over 24 weeks and peak change from baseline in FEV1 within 2 hours post-dosing over 24 weeks (Table 2). Non-inferiority for glycopyrrolate/formoterol fumarate versus umeclidinium/vilanterol was demonstrated for change from baseline in peak FEV1 within 2 hours post-dose over 24 weeks (demonstrated by the lower bound of the 2-sided 97.5% confidence interval [CI] of the least squares means [LSM] difference greater than the pre-determined margin of –50 mL), but not for change from baseline in morning pre-dose trough FEV1 over 24 weeks.
Table 2 Primary Lung Function Endpoints in Head-to-Head RCTs |
The primary endpoint in Study A2349 and Study A2350 was change from baseline in FEV1 area under the plasma concentration–time curve from 0 to 24 hours (AUC0–24h) at Week 12. In both trials, the non-inferiority of indacaterol/glycopyrrolate relative to umeclidinium/vilanterol (demonstrated by the lower bound of the 1-sided 97.5% CI of the LSM difference relative to the pre-determined margin of –20 mL) was not met (Table 2).
In Study GSK204990, the primary endpoint was change from baseline in trough FEV1 at Week 8. Umeclidinium/vilanterol was non-inferior to tiotropium/olodaterol (demonstrated by the lower bound of the 2-sided 95% CI of the LSM difference greater than the pre-specified margin of –50 mL; per-protocol population; Table 2); a subsequent analysis in the intent-to-treat population demonstrated that umeclidinium/vilanterol was superior to tiotropium/olodaterol (lower bound of the 95% CI for the treatment difference >0 mL; Table 2).
Data for secondary lung function endpoints (trough FEV1, trough FEV1 responders, FEV1 area under the plasma concentration–time curve from 0 to 12 hours [AUC0–12h], FEV1 area under the plasma concentration–time curve from 12–24 hours [AUC12–24h], trough forced vital capacity [FVC], trough inspiratory capacity [IC], and post-dose peak IC) are presented in the Supplementary Materials (Supplementary Table 2). In contrast, no lung function endpoints other than trough FEV1, peak FEV1 and FEV1 area under the plasma concentration-time curve from 0 to 4 hours (AUC0–4) were evaluated in NMAs (see "Indirect evidence: Lung function" section).
Direct Evidence: PROs
In the AERISTO study, the PROs evaluated included changes from baseline in TDI focal score and CAT scores over 24 weeks (Supplementary Table 3). Nominal non-inferiority of glycopyrrolate/formoterol fumarate versus umeclidinium/vilanterol was established for both outcomes, according to the pre-specified non-inferiority margins. Study GSK204990 evaluated change from baseline in CAT scores and E-RSCOPD scores (Supplementary Table 3). No difference between treatments was observed in change from baseline in CAT scores or E-RSCOPD scores at Week 8 between umeclidinium/vilanterol and tiotropium/olodaterol. PROs were not analyzed formally in Study A2349 and Study A2350.
Table 3 Characteristics of the Included NMAs |
Direct Evidence: Exacerbations
Time to first moderate-to-severe COPD exacerbation was evaluated as an exploratory secondary efficacy endpoint in the AERISTO study only. During the 24-week treatment period, the effect of glycopyrrolate/formoterol fumarate and umeclidinium/vilanterol on time to first moderate-to-severe exacerbation was comparable, with a hazard ratio close to 1 (hazard ratio = 0.97; 95% CI = 0.73–1.29).
Direct Evidence: Safety
The results of all four head-to-head RCTs suggested that the proportion of patients reporting any adverse events (AEs) was similar between LAMA/LABA treatment groups in each study (AERISTO: glycopyrrolate/formoterol fumarate 40.9%; umeclidinium/vilanterol 44.9%; Study A2349: indacaterol/glycopyrrolate 41.3%; umeclidinium/vilanterol 44.1%; Study A2350: indacaterol/glycopyrrolate 35.0%; umeclidinium/vilanterol 34.6%; Study GSK204990: tiotropium/olodaterol 31%; umeclidinium/vilanterol 25%). Also, where reported, the proportions of patients reporting serious AEs, treatment-related AEs, or AEs leading to discontinuation were similar between LAMA/LABA FDCs in each study.
Indirect Evidence: Study Characteristics
Following the literature review, a total of six NMAs were identified that provided indirect comparisons of LAMA/LABA FDCs (Figure 2); however, one of these was out of the pre-defined scope of this review as it included studies of short duration (3 and 6 weeks) and did not specifically report outcomes at or over 12 or 24 weeks.21 All NMAs included RCTs conducted in adult patients with stable, moderate-to-very severe airflow obstruction,15,22–25 The NMA by Aziz et al included only parallel-group RCTs.22 The NMAs by Siddiqui et al,15 Sion et al,23 Schlueter et al,24 and Huisman et al25 did not have any restriction on the design of the RCTs as both cross-over and parallel studies were included (Table 3).
The scope of each NMA varied (Table 3). For example, the NMAs by Aziz et al,22 Sion et al,23 and Huisman et al25 included RCTs with durations of ≥8 weeks, ≥10 weeks, and ≥12 weeks, respectively, whereas the NMA by Schlueter et al24 had no restrictions on the duration of the RCTs but only included those reporting outcomes of interest at 20–28 weeks and 48–52 weeks. Three of the NMAs compared several classes of inhalation therapy, including LAMA/LABA (FDCs and open combinations), inhaled corticosteroid (ICS)/LABA (FDCs and open combinations), and LAMA monotherapy, whereas the Siddiqui et al15 and Schleuter et al24 NMAs focused on the comparative efficacy of LAMA/LABA FDCs. The most recently published NMAs included a wider variety of LAMA/LABA FDCs compared with earlier NMA publications, due to the availability of new combinations. In four NMAs, the comparators of interest were any of the listed interventions and placebo, whereas in the NMA by Siddiqui et al,15 only RCTs evaluating LAMA/LABA FDCs were included.
Indirect Evidence: Quality Assessment
Results of the quality assessment demonstrated that all NMAs included populations and interventions relevant to their research objective, and identified RCTs using a comprehensive systematic literature review. Peak FEV1, FEV1 AUC0–4h, and exacerbation endpoints were generally absent from the outcomes evaluated in the NMAs, except for the Siddiqui et al15 NMA. A connected network of RCTs was formed in each of the published NMAs and included both direct and indirect comparisons. Of note, all NMAs included studies associated with a high risk of bias; these studies were either open-label or the method of randomization (or available description of the method of randomization) was not considered adequate.
All of the NMAs attempted to identify treatment effect modifiers (ie, patient characteristics that may impact the effectiveness of treatment) across the included RCTs, and three NMAs (Siddiqui et al,15 Sion et al,23 and Schlueter et al24) reported differences in the distribution of treatment effect modifiers across studies. Schlueter et al24 performed meta-regression to adjust for baseline disease severity and concomitant ICS use, whereas Sion et al23 performed subgroup analyses to control for severity of lung function impairment and baseline ICS use. Siddiqui et al15 conducted a meta-regression analysis to account for differences in baseline airflow limitation, SGRQ total score, and ICS use. Also, a subgroup analysis in symptomatic patients was performed for symptoms, quality of life, and exacerbation endpoints. From the quality assessment, the conclusions in each NMA were considered fair and balanced.
Indirect Evidence: Heterogeneity and Inconsistency
All NMAs discussed heterogeneity across the included RCTs with respect to study characteristics and patient baseline characteristics. Overall, the RCTs included in these NMAs were comparable in terms of study characteristics; however, some variations in patient sample sizes were observed. Across the NMAs, heterogeneity was observed for COPD severity, mean percentage predicted FEV1 at baseline, exacerbation history in the previous year, smoking status, concomitant ICS at baseline, mean SGRQ score at baseline, and gender.
Aziz et al22 did not find any inconsistency in the networks of any of the outcomes analyzed. Schlueter et al24 identified a potential inconsistency in the network of change from baseline in SGRQ score at 24/26 weeks, caused by two umeclidinium/vilanterol trials in which the direction of results was different. However, no explanation could be provided for this difference, because COPD severity and concomitant medication use – factors that could potentially contribute to differences in treatment effects – were similar in both trials. Siddiqui et al15 identified potential inconsistencies in the networks of TDI responders at 24 weeks for the comparison of glycopyrrolate/formoterol fumarate versus umeclidinium/vilanterol. There was also a potential inconsistency between direct and indirect evidence for trough FEV1, which may reflect the differential results observed in the direct evidence (AERISTO study; note that this study was only included in the Siddiqui et al15 NMA due to its more recent search timeframe).
Indirect Evidence: Lung Function
Only trough FEV1, peak FEV1 and FEV1 AUC0–4 were evaluated in NMAs; therefore, the results of the other lung function endpoints are not discussed. All five of the included NMAs evaluated change from baseline in trough FEV1 as an outcome. In general, the LAMA/LABA FDCs appeared comparable with each other in improving change from baseline in trough FEV1 at 24/26 weeks (Table 4 and Supplementary Table 4). Results for change from baseline in trough FEV1 at 24/26 weeks were inconsistent between the NMAs specifically for the comparison of aclidinium/formoterol fumarate with the other FDCs of glycopyrrolate/indacaterol, tiotropium/olodaterol, and umeclidinium/vilanterol, with some comparisons reaching statistical significance (Table 4).
Table 4 NMA Results for Change from Baseline in Trough FEV1 at 24/26 Weeks for Each Treatment Comparison by Studya |
Change from baseline in peak FEV1 and FEV1 AUC0–4h were only evaluated in the Siddiqui et al NMA. At 24 weeks, the magnitude of the effect of the change from baseline in peak FEV1 was generally comparable between the LAMA/LABA FDCs; however, a statistically significant difference in favor of glycopyrrolate/formoterol fumarate versus umeclidinium/vilanterol was seen (Supplementary Table 5). With respect to change from baseline in FEV1 AUC0–4h at 24 weeks, all LAMA/LABA FDCs appeared comparable, with mean treatment differences being statistically non-significant for each comparison (range –5.2 mL with umeclidinium/vilanterol vs glycopyrrolate/indacaterol to 4.6 mL with glycopyrrolate/indacaterol vs glycopyrrolate/formoterol fumarate; Supplementary Table 6).
Indirect Evidence: PROs
TDI focal score and changes from baseline in SGRQ scores at 24/26 weeks were analyzed in all five included NMAs (Supplementary Tables 7 and 8),15,22–25 and the proportions of TDI and SGRQ responders at 24/26 weeks15,22,24 were analyzed in three NMAs (Supplementary Tables 9 and 10). The LAMA/LABA FDCs analyzed were all comparable in relation to improvements in these endpoints (Supplementary Tables 7–14).
Indirect Evidence: Exacerbations
Of the five included NMAs identified in the literature review, only the Schlueter et al24 and Siddiqui et al15 NMAs evaluated rates of moderate-to-severe COPD exacerbations (Supplementary Tables 15 and 16). No statistically significant differences were observed between glycopyrrolate/formoterol fumarate, glycopyrrolate/indacaterol, tiotropium/olodaterol, and umeclidinium/vilanterol in terms of reduction in the rate of moderate-to-severe exacerbations.
Indirect Evidence: Safety
The incidence of any AEs was analyzed in two NMAs,15,22 and discontinuations due to AEs were analyzed in one NMA.24 In these NMAs, the LAMA/LABA FDCs generally had comparable safety profiles with respect to these outcomes.
All-cause discontinuations were analyzed in two NMAs,15,24 with findings suggesting that the LAMA/LABA FDCs evaluated were generally comparable; however, in the NMA by Schlueter et al,24 a statistically significant difference in all-cause discontinuations at 24/26 weeks was observed in favor of tiotropium/olodaterol versus umeclidinium/vilanterol.
Current treatment recommendations (GOLD 2020) for the use of LAMA/LABA FDCs in COPD provide guidance for the use of these agents as a class and do not differentiate between therapies within this class.4 These literature reviews were conducted to assess direct and indirect evidence for improvements in lung function, PROs, and safety with LAMA/LABA FDC therapies in patients with moderate-to-very severe airflow limitations in COPD.
From the review of direct evidence, it was apparent that few pairs of LAMA/LABA FDCs have been compared directly in head-to-head clinical trials. In total, only four RCTs were identified, all of which included umeclidinium/vilanterol as one of the treatments, and most of which focused primarily on lung function.
In terms of the primary endpoints, the non-inferiority of glycopyrrolate/formoterol fumarate versus umeclidinium/vilanterol was demonstrated in the AERISTO study for change from baseline in peak FEV1 but not trough FEV1 over 24 weeks. However, the lung function response with glycopyrrolate/formoterol fumarate in the AERISTO study was lower than that observed in previous studies of this combination.18 In Study A2349 and Study A2350, indacaterol/glycopyrrolate was not non-inferior to umeclidinium/vilanterol in change from baseline in FEV1 AUC0–24h at Week 12, which may have been due to the narrow non-inferiority margin of –20 mL.19 In Study GSK204990, umeclidinium/vilanterol was superior to tiotropium/olodaterol in change from baseline in trough FEV1 at Week 8.20
Notable differences between the methodological and clinical characteristics were identified across the head-to-head studies included in the literature review. For example, study durations varied from 8 to 24 weeks, airflow limitation inclusion criteria varied from moderate only to moderate-to-very severe, and the blinding was different across the studies, such that AERISTO, Study A2349, and Study A2350 were double-blind trials while Study GSK204990 was an open-label trial (with an associated high risk of bias). Also, a non-inferiority margin of 50 mL was used for trough FEV1 in the AERISTO study and Study GSK204990, while the non-inferiority margin used for FEV1 AUC0–24h in the Kerwin et al19 studies (Study A2349 and Study A2350) was notably narrow (20 mL) and may have contributed to the failure to demonstrate non-inferiority. Moreover, the two studies that included glycopyrrolate/indacaterol as a treatment arm were conducted in the USA and administered the 15.6/27.5 µg twice-daily (BID) dose,19 which is only available in the USA. This inconsistency in the design of the head-to-head RCTs, as well as differences in the included patient population and endpoints reported and the inclusion of limited LAMA/LABA FDCs in these studies, some with a US-only dosing regimen, makes it difficult to draw generalizable, overarching conclusions regarding the comparative effectiveness of LAMA/LABA FDCs in patients with COPD from the direct comparisons alone.
With this scenario, a second literature review was undertaken to evaluate indirect evidence from NMAs, which allowed additional information on treatment comparisons to be obtained. NMAs allow direct and indirect evidence to be combined and, by linking data from RCTs through common treatment arms, allow trends in results across different trials to be assessed.26 Furthermore, NMAs have the potential to assess a greater variety of endpoints from a larger evidence base compared with the direct, head-to-head evidence.26
In contrast to the head-to-head RCTs, all five included NMAs identified in the literature search concluded that the different LAMA/LABA FDCs were generally comparable in terms of lung function improvements. Although certain statistically significant differences in trough and peak FEV1 were identified for some comparisons, the treatment differences were considered small, relative to established margins of clinical significance.27
Although FEV1 outcomes were the primary endpoints in all four head-to-head RCTs, it is known that airflow limitation is poorly related to other important clinical measures, such as symptoms and health status, due to the heterogeneous nature of COPD.28 The two key goals of COPD treatment, as outlined in the GOLD report, are to reduce symptoms and the future risk of exacerbations.4 Where assessed, the results of this review demonstrate that LAMA/LABA FDCs have comparable efficacy in improving symptoms, quality of life, and exacerbations when assessed in head-to-head studies. However, it should be noted that quality of life and symptoms were only assessed in two of the four head-to-head studies,18,20 and exacerbations were only assessed as an exploratory efficacy outcome in the AERISTO study.18 Moreover, none of the head-to-head studies assessed health status using SGRQ, a disease-specific health-related quality of life questionnaire. With respect to the indirect evidence, our review demonstrated that although the five included NMAs identified in the literature assessed different endpoints, investigation of endpoints that were not consistently reported in the head-to-head studies (TDI focal score, SGRQ, and exacerbations) was possible and enabled a greater number of LAMA/LABA FDCs to be compared. Consistent with the direct evidence, all NMAs identified in the literature search concluded that the different LAMA/LABA FDCs were generally comparable in terms of PROs and safety.15,22–25
While indirect evidence provides some additional information over head-to-head studies, it is important to note the inherent limitations of NMAs, such as concerns of bias, heterogeneity, precisions, and uncertainty in the estimated efficacies.26 It should be noted that only one of the five included NMAs (Siddiqui et al15) reported lung function outcomes other than trough FEV1, meaning that limited comparisons for lung function could be described in this literature review. Also, in the individual NMAs, very few studies could be included for the analyses of exacerbations, meaning there are high levels of uncertainty around these results.
In conclusion, from the systematic literature review, a limited number of head-to-head RCTs comparing LAMA/LABA FDCs in patients with COPD with moderate-to-very severe airflow limitation were identified. These head-to-head studies varied in design, endpoints, and baseline patient characteristics and evaluated a limited range of LAMA/LABA FDC comparisons. Additional information on the relative efficacy of LAMA/LABA FDCs was obtained from indirect comparisons in NMAs. Although there were some inconsistencies between the outcomes of the RCTs and NMAs for trough FEV1, the totality of lung function, symptoms, exacerbations, and safety data presented suggests that the available LAMA/LABA FDCs have comparable efficacy and safety in patients with COPD and moderate-to-severe airflow limitation. Given this, we suggest other factors such as patient preference and ability to use the device may be important when physicians are considering treatment choice within the class.
AE, adverse event; AECOPD, acute exacerbations of chronic obstructive pulmonary disease; AUC, area under the plasma concentration–time curve; BID, twice daily; CAT, COPD Assessment Test; CI, confidence interval; CrI, credible interval; CSR, clinical study report; E-RSCOPD, Evaluating Respiratory Symptoms COPD; FDC, fixed-dose combination; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IC, inspiratory capacity; ICS, inhaled corticosteroids; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; LSM, least squares means; MDI, metered dose inhaler; NA, not applicable; NI, non-inferiority; NMA, network meta-analysis; NR, not reported; OD, once daily; PRO, patient-reported outcome; RCT, randomized controlled trial; SAMA, short-acting muscarinic antagonist; SE, standard error; SGA, subgroup analysis; SGRQ, St. George's Respiratory Questionnaire; TDI, Transition Dyspnea Index.
Data Sharing Statement
Not applicable.
Ethics Approval and Consent
Not applicable.
Medical writing support, under the direction of the authors, was provided by Karleen Nicholson, PhD, on behalf of CMC Connect, and Jake Casson, PhD, CMC Connect, McCann Health Medical Communications, funded by AstraZeneca, Gaithersburg, USA in accordance with Good Publication Practice (GPP3) guidelines.29
Author Contributions
All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.
JRH reports personal payments and payments to UCL for educational and advisory work and support to attend meetings, and grant support to UCL from pharmaceutical companies that make medicines to treat COPD, including AstraZeneca. KG-J has been a speaker for and consultant to AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mundipharma, Novartis, Pfizer, and Teva. During the conception and design of the study, KG-J was contracted to AstraZeneca and received a fee for services. MB, DG, MJ, and NS are employees of AstraZeneca and hold stock and/or stock options in the company. AB is an employee of Parexel International Ltd, the organization that received funding from AstraZeneca to perform the systematic review. The authors report no other conflicts of interest in this work.
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5. Bogart M, Stanford RH, Laliberté F, Germain G, Wu JW, Duh MS. Medication adherence and persistence in chronic obstructive pulmonary disease patients receiving triple therapy in a USA commercially insured population. Int J Chron Obstruct Pulmon Dis. 2019;14:343–352.
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19. Kerwin E, Ferguson GT, Sanjar S, et al. Dual bronchodilation with indacaterol maleate/glycopyrronium bromide compared with umeclidinium bromide/vilanterol in patients with moderate-to-severe COPD: results from two randomized, controlled, cross-over studies. Lung. 2017;195(6):739–747.
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24. Schlueter M, Gonzalez-Rojas N, Baldwin M, Groenke L, Voss F, Reason T. Comparative efficacy of fixed-dose combinations of long-acting muscarinic antagonists and long-acting β2-agonists: a systematic review and network meta-analysis. Ther Adv Respir Dis. 2016;10(2):89–104.
25. Huisman EL, Cockle SM, Ismaila AS, Karabis A, Punekar YS. Comparative efficacy of combination bronchodilator therapies in COPD: a network meta-analysis. Int J Chron Obstruct Pulmon Dis. 2015;10:1863–1881.
26. Tonin FS, Rotta I, Mendes AM, Pontarolo R. Network meta-analysis: a technique to gather evidence from direct and indirect comparisons. Pharm Pract. 2017;15(1):943.
27. Jones PW, Beeh KM, Chapman KR, Decramer M, Mahler DA, Wedzicha JA. Minimal clinically important differences in pharmacological trials. Am J Respir Crit Care Med. 2014;189(3):250–255.
28. Agusti A, Calverley PM, Celli B, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res. 2010;11:122.
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© 2020 The Author(s). This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.


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Israeli Travel Tech Companies Fornova and HotelsBI Announce Merger
Fornova will integrate HotelsBI's hotel performance analytics software into its suite of products aimed at the hospitality industry
Fornova Ltd. has acquired Hotels BI Ltd., the two Israel-based travel tech companies announced Monday. The financial terms of the deal were not disclosed.
As part of the deal, Fornova will integrate HotelsBI's hotel performance analytics software into its suite of products. Tel Aviv-based HotelsBI was founded in 2016.
Founded in 2010 and based in the northern Israeli town of Yokneam, Fornova offers businesses in the hospitality industry online monitoring and optimization of performance and distribution. The company employs over 100 people in offices in Israel, the U.S., and Europe, according to company statements. Fornova has raised $18 million to date, according to Pitchbook data.
Fornova co-founders Michael Rubanovich (left), Dori Stein, and Dima Babitsky. Photo: Noa Zeni


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Q: On Appeal to District Appellate Court my case was VACATED and REMANDED back to the Bankruptcy Court. The Court REFUSED.
The Bankruptcy Court said I owed
Payment s to my plan . My case was ruled against me and ended before the Appeal the Appellate Court decided the Vacate Remand Order. The Bankruptcy Judge who did so was removed from his cases before he made the decision.
I have unquestionable evidence of Fraud on the Court. Case involved
$500,000 owed me from the sale of my buy to a NASDAQ Corp.
This question was posted as a question on patents (inventions). That is not the right topic. You may get better answers if you post this as a bankruptcy question.
Good Luck
Kevin E Flynn
A: You should ask your bankruptcy attorney, if you have one. If the bankruptcy order was vacated and remanded, it means that the bankruptcy court (another judge, apparently) is to consider the issue again.
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Ask any real estate agent which words tend to be red flags on listings, and one word will come up before you can even finish your question: cozy. It's long been code for conveying how small (and, potentially, cramped) a home can be, but it seems attitudes toward the word are starting to change. When design service Modsy surveyed more than 1,500 people on the hallmarks of a well-designed home, one word was uttered the most: cozy.
So, what changed? Our entire view of our homes, thanks to the pandemic. As the world felt more uncertain than ever, we turned inward, craving a sense of sanctuary (just see the rising interest in creating spa-like bathrooms and escapist decor). "Just as the fashion world is all about coziness, with athleisure taking center stage for what we're wearing, people are asking the interior design world to create environments that promote comfort as well," Modsy explained in its 2021 Wellness Report.
We're all looking for a place where we can feel at ease, so it's fitting that the word "calm" was a close second as a sign of a well-designed space (followed by "organized" and "relaxed"). The challenge, though, is striking a balance between the two: How do you make a space feel comfy without looking cluttered? Or Zen without skewing stark? We have a few suggestions.


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Antisocial behaviour and nuisance
Antisocial behaviour (ASB) is anything that intimidates, causes distress or alarm or significantly reduces someone's quality of life.
The types of behaviour that could be deemed antisocial can include: abandoned vehicles, dog fouling, fly tipping, graffiti, littering, noise nuisance and neighbour disputes.
Where the required evidence thresholds are met, the council are able to conduct investigations that enable the use of various tools and powers, in accordance with the different legislation that is available to the council.
Please be aware that the contact details listed in the right hand pane are not not monitored outside of office hours or for use in an emergency.
If a crime is in progress, dial 999. You can also report crimes on the non-emergency police number 101 or online at Suffolk Constabulary - report anti-social behaviour
For more information and details on how to report to the correct department please click on the relevant link below.
An authorised officer will inspect and determine whether they consider a vehicle to be abandoned or not.
If you are a dog owner or walker then you must pick up your dog's mess if it fouls in a public place. This is a legal requirement as described in Public Spaces Protection Order (Dogs) 2017. If you do not then you may be issued with a Fixed Penalty Notice. If you do not pay the Fixed Penalty Notice then you could be taken to court and fined up to £1000.
Dumping waste on any land which doesn't have an Environmental Permit, or allowing others to do so on your behalf is a criminal offence. You could face very large fines and even be sent to prison.
Graffiti is writing or drawings scribbled, scratched, or sprayed illicitly on the surface of any property and is an act of vandalism which is a criminal offence under the Criminal Damage Act 1971, and carries a large fine or imprisonment on conviction. For minor incidents an £80 on the spot fixed penalty notice may be issued to offenders.
Help us keep west Suffolk a litter free zone by putting your rubbish in the bins provided. Under the Environmental Protection Act 1990 those caught littering can be issued a fixed penalty notice of £80 rising to £2,500 if this is taken to court.
Loud noises can cause upset and distress to people in their homes. If you are having problems with excessive noise, from a neighbour in a domestic property or a business, then there are things that you can do to help solve the problem.
If you are not sure where to report an issue you are experiencing you can complete our antisocial behaviour report form online or phone us to report antisocial behaviour in West Suffolk.
If you have already reported ongoing antisocial behaviour (ASB) to either the Police, your district or borough council or your housing provider and you feel that no action has been taken to resolve it, you can activate the ASB Case Review through the ASB Case Review referral form and ask us to request a review of your case.


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Imperial 124C Refrigeration and Air Conditioning Service Wrench
- Manufacturer:
- Imperial
- Price:
- $20.95
- Shipping Cost:
- Contact Us
Product Details
Imperial 124-C Refrigeration Wrench.
Rugged, steel forged wrench with four sizes covering almost any application.
9/16" hex for dust cap on access valves and plug oil check on comressor;
1/2" hex for compressor mounting bolts;
1/4" square for valve stem and service valves and old style compressor valves;
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Made in USA.
Air Conditioning and Refrigeration service Tech specialty hand tools


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The new year has kicked off with a slew of negative crypto news. Now more than ever, for every one trustworthy source on crypto, there seems to be hundreds of YouTubers spewing less-than credible "advice." Videos that appear to be unbiased explainers will end with a segment selling you hard on specific investments. As with all things money-related, it's important to remember that most so-called gurus are going to give advice that's better for them than it is for you. Most of the crypto-related videos online should be viewed through a lens of entertainment purposes, and should not be relied on for, tax, legal or accounting advice.
That being said, it doesn't hurt to see what's out there—whether you're learning how the blockchain works for the first time, or you're looking for 2023-specific advice to make the most of your investments. Although my YouTube journey didn't convert me into a crypto-head, perhaps where I fostered my skepticism, you'll find inspiration. Here's a round-up of some of the most helpful video explainers on the topic, so you can give yourself a crash course in all things cryptocurrency.
How does blockchain work (Simply Explained)
Before you dive into buying and selling specific crypto, you really should understand the basic mechanisms behind cryptocurrency. As IBM explains it, blockchain is "a shared, immutable ledger that facilitates the process of recording transactions and tracking assets in a business network." But if you're like me, that explanation doesn't instantly make a ton of sense. In that case, the video above from creator Simply Explained does a good job of putting the concept of blockchain into accessible terms.
Cryptocurrency explained (CBS News)
Now that you understand the basics of blockchain, it helps to get a more focused overview on how cryptocurrency works in practice. This clip is easy-to-digest and, generally speaking, it's news sources (like CBC News featured above) that should be your go-to for a baseline crypto explainer. Like we mentioned in the intro, it's all too easy to click on a supposedly unbiased video that eventually tries to sell you on a specific currency.
Bitcoin Trading for Beginners: A Guide in Plain English (99Bitcoins)
Now that you understand the basics, it's time to apply them to the actual process of trading Bitcoin. Bitcoin trading is the act of buying low and selling high. Unlike investing, which means holding Bitcoin (or another cryptocurrency) for the long run, trading deals with trying to predict price movements by studying the industry as a whole and price graphs in particular.
This video from 99Bitcoins goes into how to trade Bitcoin, provides a glossary of terms, explains how to read price graphs, and offers common trading mistakes (like risking more money than you can afford to lose).
How cryptocurrency actually works (Mrwhosetheboss)
Even if you aren't fully onboard the crypto train, it's wise to educate yourself on the sort of knowledge others are eating up—like the 13 million others who subscribe to tech YouTuber Mrwhosetheboss. Compared to the videos on the previous slides, this one is far more in-depth, diving into the specifics of Bitcoin, Dogecoin, Ethereum, and NFT's. If you're only going to watch a few minutes of this video, I recommend skipping the beginning and opting for about ten minutes in, when there's a useful "dark side" segment about the problems and oddities that come with crypto.
How to invest in crypto full beginners guide in 2023 (Brian Jung)
If, after all of those, you are still interested in buying crypto, this guide has up-to-date tips for beginners. Jung is a YouTuber who focuses on videos on crypto and personal finance. Although his status as an investor is a sign to take his recommendations with a grain of salt, he does have generally useful advice, like the urging other investors to get a security key.
Understanding The Rise And Fall Of FTX, FTT And Alameda Research (Forbes)
Finally, whatever your stance on crypto, it's important to understand what the hell is going in the landscape right now. This 20-minute feature from Forbes explains one of the biggest scandals in crypto right now: The fall of FTX. As the video explains, the fall of FTX and Sam Bankman-Fried "revealed holes in the crypto space that industry peers, the media, and government officials either chose to overlook or refused to question further." Anyone drawn in by crypto would be wise to learn about how fragile an ecosystem it can be.
And a bonus: Line Goes Up—The Problem With NFTs (Folding Ideas)
Though this oft-shared, in-depth video essay deals more directly with NFTs than Bitcoin, many of the same lessons apply to both markets, as both operate on many of the same principles and technologies. Also, it shows up in the comments on every article about the subject, so I might as well head someone off at the pass. It truly is a fascinating dive into the mindset driving (at least some) investors to risk so much in a still largely untested, uncertain, and unregulated market.


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Learning from Each Other, Dreaming the Future
What environmental education practices are inspiring and effective when creating cultures grounded in equity and inclusion? Join the Center for Diversity & the Environment, in partnership with NAAEE ee360+, for a conversation with leading environmental educators as they share stories and explore what is bright, alive, and necessary in EE grounded in equity, diversity, inclusion, justice, and liberation.
To join, please complete the survey to receive a Zoom invite.


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AFC Wimbledon 2 Southend United 1 – Pinnock seals huge win for League One strugglers
After eight successive League One defeats, Wimbledon finally had a slice of luck as Mitch Pinnock's intended cross dropped into the Southend goal to decide a poor encounter that nevertheless throws the hosts a lifeline.
An open start had seen Theo Robinson sting Dons keeper Joe McDonnell's palms at the near post and Pinnock blaze wildly over, unmarked, from a Kwesi Appiah lay-off at the other end inside the opening eight minutes.
Less than a minute later, the hosts were behind when a low cross from Southend's Stephen Hendrie on the left was sidefooted past McDonnell at his near post by the hapless Liam Trotter, facing his own goal.
Deji Oshilaja fired wildly over on the run, from a similar position to Pinnock midway through the first half, but Wimbledon were looking second best.
Somehow they went in on level terms at the break though, after Scott Wagstaff crossed from the right and snookered Hendrie, who headed home as Oshilaja wheeled away in delight.
The Dons skipper had to get his body on the line in the 59th minute to block a shot by Robinson as the second half started to drift.
Wimbledon finally got a break in the 70th minute, as Pinnock's curling cross from the right caught out United keeper Mark Oxley – distracted by the run of first-half substitute Joe Pigott – and sailed around the shot-stopper to drop into the bottom left corner of the goal.
A falling Pigott came within a whisker of a third goal nine minutes later, firing against the left-hand upright after a Pinnock corner from the right ricocheted between the heads of Oshilaja and Will Nightingale at the far post before being hacked off the line by an orange shirt.
With Wimbledon visibly gaining in confidence, Wagstaff broke down the right a minute from time – despite a tug from Harry Kyprianou – and crossed for Pigott, whose header was blocked on the line by John White.
AFC Wimbledon (4-2-3-1): McDonnell, Oshilaja, Nightingale, McDonald, Purrington, Soares, Trotter, Pinnock (Barcham, 90), Wordsworth (Hartigan, 90), Wagstaff, Appiah (Pigott, 43). Subs not used: King (GK), Watson, Thomas, Jervis.
Southend United (5-3-2): Oxley, Demetriou, Moore, White, Kyprianou, Hendrie (McLaughlin, 82) Mantom, Dieng, Yearwood (Bunn, 61), Robinson (McCoulsky 61), Cox. Subs not used: Bishop (GK), Bwomono, Hyam, Kightly.
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