Biofourmis and Beacon Health System have partnered for an in-home monitoring program specifically meant for patients with complex chronic diseases, including chronic obstructive pulmonary disease (COPD), during their post-discharge period.

Patient-reported data will be automatically collected, analyzed, and presented in a continuously updated dashboard visible to clinicians. This remote monitoring program aims to reduce hospital readmissions, improve clinical outcomes, and expand care access.

Patients with congestive heart failure are also eligible to be enrolled in the program in the first year, which will be launched across Elkhart General Hospital and Memorial Hospital, two of Beacon’s largest hospitals. Based on early results, the program is expected to expand to larger patient populations with other health conditions.

“With the Biofourmis solution, our patients with congestive heart failure or COPD can be discharged home safely and will be monitored more closely to prevent the need for readmission,” Sam El-Dalati, MD, chief clinical officer at Beacon, said in a press release.

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COPD breathing worse at night | COPD News Today | surveys illustration

Estimated 16 million people live with COPD in US

COPD is a chronic inflammatory disease of the lungs characterized by air flow blockage associated with long-term exposure to lung irritants, mainly cigarette smoke. It is estimated that 16 million Americans are living with COPD, a disease that leads to more than 650,000 hospitalizations per year. Statistics also indicate that 20% of patients diagnosed with COPD end up being readmitted to the hospital within 30 days of being discharged.

The remote patient monitoring program includes Biovitals, a Biofourmis advanced analytics platform, along with patient-facing digital tools, a clinician dashboard with a mobile interface, medical devices and equipment, logistics, and clinical services.

With the Biovitals Analytics Engine, patients are evaluated based on their own clinical baseline data. This helps Beacon providers to evaluate each patient’s trajectory on the dashboard, where they are notified of any significant changes.

The platform’s goal is to simplify healthcare and improve patient health, by providing in-home access to hospital-level services, virtual provider networks for remote care, and innovative clinical trials. This may help to prevent hospital readmissions and accelerate therapy development.

“The solution will enable us to remotely monitor patients’ conditions, respond to symptoms, assist with medications and even conduct telehealth visits. Together, these tools will help us ensure these patients transition to home safely following their hospitalizations,” said John Bruinsma, manager of care coordination at Beacon.

Beacon providers will receive remote support from Biofourmis’ multidisciplinary care team, which includes qualified physicians, nurses, care navigators, and respiratory technicians, who will assist with patient monitoring and interventions, mainly overnight and on weekends.

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“Leading, innovative health systems like Beacon understand that preventing readmissions and improving outcomes for patients with complex chronic conditions requires next-generation monitoring, patient education and proactive clinical interventions,” said Maulik Majmudar, MD, chief medical officer and co-founder of Biofourmis.

“Biofourmis is supporting Beacon’s important initiative by delivering a continuously updated view of each patient’s health along with actionable care insights and a skilled clinical team to yield better outcomes while expanding access to care by allowing patients to remain at home,” Majmudar said.

Over the next months, Beacon physicians and teams from several fields of specialty will work together to plan, develop, and launch the program. The monitoring program is being supported by funding Beacon obtained from the Coronavirus Aid, Relief, and Economic Security Act, which is part of the COVID-19 Telehealth Program.

Beacon is the largest local non-profit health system across northern Indiana and southwest lower Michigan, with 146 care sites, including eight hospitals with 1,240 beds, across seven counties. It has nearly 8,000 associates and more than 1,175 physicians and other providers who care for more than 4,000 patients a day.

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Models that include objective brain markers of breathlessness-expectation have the ability to predict, for the first time, which patients will experience clinically important improvements in chronic obstructive pulmonary disease (COPD)-linked breathlessness during pulmonary rehabilitation, according to clinical trial results published in Thorax.

Recognizing that baseline patient characteristics predictive of breathlessness remain unknown, the investigators sought to evaluate functional brain imaging markers of breathlessness-expectation as predictors of therapeutic response to pulmonary rehabilitation. Toward that end, the researchers assessed whether the brain-active agent D-cycloserine — which is known to influence expectation mechanisms — was able to modulate any predictive model.

The investigators conducted a randomized, controlled, double-blind, experimental medicine study (ClinicalTrials.gov identifier: NCT01985750) of D-cycloserine administered during pulmonary rehabilitation. The study evaluated 71 participants (18 female; average age, 71 years [range, 46 to 85 years]) with mild to moderate COPD who were recruited immediately prior to enrollment in a National Health Service-prescribed course of pulmonary rehabilitation. Baseline variables, including brain activity, clinical measures of pulmonary function, responses from self-report questionnaires, and drug allocation, were used to train machine-learning models to predict the outcome — which was a minimally clinically relevant change in the Dyspnea-12 (D-12) score.

Data for the current analysis were obtained at a baseline evaluation occurring at the beginning of a pulmonary rehabilitation course as well as at another evaluation performed upon completion of the pulmonary rehabilitation at 6 to 8 weeks. After the initial visit, the participants were randomly assigned to receive either oral D-cycloserine 250 mg or matched placebo. All of the participants received a single dose on 4 separate occasions 30 minutes prior to the onset of the first 4 pulmonary rehabilitation sessions. At baseline, the median Medical Research Council (MRC) DP-12 breathlessness score of the participants was 3, the median forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) was 0.55, and the median FEV1 percent predicted was 58.

Based on MRC DP-12 scores, participants were classified as “responders” (ie, those having a score of ≥3) or “nonresponders.” Overall, 41 of 71 participants in the primary dataset were classified as responders (24 in the D-cycloserine group and 17 in the placebo group), whereas 30 were nonresponders (13 in the D-cycloserine group and 17 in the placebo group). No statistically significant interaction between the responders and the nonresponders and the drug was identified with the use of χ2 analysis (P =.21).

We have shown that models including objective brain markers of breathlessness-expectation are able to predict, for the first time, which patients will have clinically important improvements in breathlessness over pulmonary rehabilitation.

Only models that included brain imaging markers of breathlessness-expectation had the ability to successfully predict improvements in D-12 score (sensitivity, 0.88; specificity, 0.77). The use of D-cycloserine was independently associated with improvement in breathlessness. Additionally, models that included questionnaires and clinical measures only did not predict outcomes (sensitivity, 0.68; specificity, 0.20).

A key limitation of the current study is the lack of validation of the model in an external dataset. Models with a large number of measures compared with events are associated with the risk for overfitting and demonstrate poor generalizability to novel datasets.

“We have shown that models including objective brain markers of breathlessness-expectation are able to predict, for the first time, which patients will have clinically important improvements in breathlessness over pulmonary rehabilitation,” the study authors concluded. “Such models could provide new insights into the mechanisms by which breathlessness may be targeted, paving the way for targeted behavioural and pharmacological interventions,” the researchers added.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

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Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about receiving this vaccine,
speak to your doctor or pharmacist.

 

This vaccine is new or being used differently. Please report side effects. See the
full CMI for further details.

Why am I being given COMIRNATY Original/Omicron BA.4-5?

COMIRNATY Original/Omicron BA.4-5 is a vaccine given as a booster dose to prevent
coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) in individuals 12 years of age and older. COMIRNATY Original/Omicron
BA.4-5 contains the active ingredients tozinameran and famtozinameran. For more information,
see Section 1. Why am I being given COMIRNATY Original/Omicron BA.4-5? in the full CMI.

What should I know before I am given COMIRNATY Original/Omicron BA.4-5?

You should not be given COMIRNATY Original/Omicron BA.4-5 if you have had an allergic
reaction to any of the ingredients in the vaccine. See list at the end of the CMI.
Check with your doctor if you have had: a severe allergic reaction or breathing problems
after any other vaccine or after being given COMIRNATY in the past; fainted following
any needle injection; a severe illness or infection with high fever; a weakened immune
system or are on a medicine that affects your immune system; a bleeding disorder,
bruise easily or are on a blood thinning medicine. As with any vaccine, COMIRNATY
Original/Omicron BA.4-5 may not fully protect all those who receive it, and it is
not known how long you will be protected. Talk to your doctor if you have any other
medical conditions, take any other medicines, or are pregnant or plan to become pregnant
or are breastfeeding. This vaccine should not be given to children under 12 years.
For more information, see Section 2. What should I know before I am given COMIRNATY Original/Omicron BA.4-5? in the full CMI.

What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any
medicines, vitamins or supplements that you buy without a prescription. Tell your
doctor or pharmacist if you have recently received any other vaccine. For more information,
see Section 3. What if I am taking other medicines? in the full CMI.

How will I be given COMIRNATY Original/Omicron BA.4-5?

COMIRNATY Original/Omicron BA.4-5 will be given as an injection into the muscle of
your upper arm by a doctor, nurse or pharmacist. You will be given one dose at least
3 months after the primary course. A doctor, nurse or pharmacist will observe you
for at least 15 minutes after being given the vaccine. COMIRNATY Original/Omicron
BA.4-5 is only given as booster doses. For primary vaccination, ask your doctor or
pharmacist. For more information, see Section 4. How will I be given COMIRNATY Original/Omicron BA.4-5? in the full CMI.

What should I know while being given COMIRNATY Original/Omicron BA.4-5?

Things you should know

An initial dose of COMIRNATY Original/Omicron BA.4-5 may be given as a booster at
least 3 months after the primary vaccination for people 12 years of age and older.

COMIRNATY Original/Omicron BA.4-5 may also be given to individuals 12 years of age
and older at least 3 months after a previous booster dose of any COVID 19 vaccine.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how the vaccine
affects you. Some of the side effects of the vaccine may temporarily affect your ability
to drive or use machines.

Are there any side effects?

Very common side effects of COMIRNATY Original/Omicron BA.4-5 include pain/swelling
at injection site, tiredness, headache, muscle pain, chills, joint pain and fever.
For more information, including what to do if you have any side effects, see Section
6. Are there any side effects? in the full CMI.
This vaccine is subject to additional monitoring. This will allow quick identification
of new safety information. You can help by reporting any side effects you may get.
You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems .

Active ingredients:
tozinameran and famtozinameran

This vaccine has provisional approval in Australia as a booster dose to prevent COVID-19 disease caused by SARS-CoV-2 virus
in individuals 12 years of age and older. This approval has been granted on the basis
of short term safety and efficacy data. Evidence of longer term efficacy and safety
from ongoing clinical trials and vaccination in the community continues to be gathered
and assessed.

Consumer Medicine Information (CMI)

This leaflet provides important information about using COMIRNATY Original/Omicron
BA.4-5. You should also speak to your doctor or pharmacist if you would like further information
or if you have any concerns or questions about receiving COMIRNATY Original/Omicron
BA.4-5.

Where to find information in this leaflet:

Why am I being given COMIRNATY Original/Omicron BA.4-5?

COMIRNATY Original/Omicron BA.4-5 contains the active ingredients tozinameran and
famtozinameran.
COMIRNATY Original/Omicron BA.4-5 is an mRNA (messenger ribonucleic acid) vaccine.

COMIRNATY Original/Omicron BA.4-5 is a vaccine given as a booster dose to prevent
COVID-19 disease caused by SARS-CoV-2 virus in individuals 12 years of age and older.

COMIRNATY Original/Omicron BA.4-5 is only given as booster doses. For primary vaccination,
ask your doctor or pharmacist.

COMIRNATY Original/Omicron BA.4-5 works by triggering your immune system to produce
antibodies and blood cells that work against the virus, to protect against COVID-19
disease.

What should I know before I am given COMIRNATY Original/Omicron BA.4-5?

Warnings

COMIRNATY Original/Omicron BA.4-5 should not be given:

1. if you are allergic to tozinameran, famtozinameran or any of the ingredients listed
at the end of this leaflet.

Check with your doctor if you have:

had a severe allergic reaction or breathing problems after any other vaccine or after
being given COMIRNATY in the past.

fainted following any needle injection.

a severe illness or infection with high fever. However, you can have your vaccination
if you have a mild fever or upper airway infection like a cold.

a weakened immune system, such as due to HIV infection or are on a medicine that affects
your immune system.

a bleeding disorder, bruise easily or are on a blood thinning medicine.

During treatment, you may be at risk of developing certain side effects. It is important
you understand these risks and how to monitor for them. See additional information
under Section 6. Are there any side effects?

Very rare cases of myocarditis (inflammation of the heart muscle) and pericarditis
(inflammation of the lining outside the heart) have been reported after vaccination
with COMIRNATY. The cases have mostly occurred within two weeks following vaccination,
more often after the second vaccination, and more often occurred in younger men. Following
vaccination, you should be alert to signs of myocarditis and pericarditis, such as
breathlessness, palpitations and chest pain, and seek immediate medical attention
should these occur.

You may develop a temporary, stress-related response associated with the process of
receiving your injection. This may include dizziness, fainting, sweating, increased
heart rate and/or anxiety. If you start to feel faint at any time during the process
of receiving your injection, let your doctor, nurse or pharmacist know and take actions
to avoid falling and injuring yourself, such as sitting or lying down.

As with any vaccine, COMIRNATY Original/Omicron BA.4-5 may not fully protect all those
who receive it, and it is not known how long you will be protected.

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to
have a baby, ask your doctor or pharmacist for advice before you receive this vaccine.

Children and adolescents

COMIRNATY Original/Omicron BA.4-5 should not be given to children under 12 years.

What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking, have recently taken or might take
any other medicines, including any medicines, vitamins or supplements that you buy
without a prescription from your pharmacy, supermarket or health food shop.

Tell your doctor or pharmacist if you have recently received any other vaccine.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins
or supplements you are taking and if these affect, or are affected by, COMIRNATY

Original/Omicron BA.4-5.

How will I be given COMIRNATY Original/Omicron BA.4-5?

COMIRNATY Original/Omicron BA.4-5 will be given as an injection into the muscle of
your upper arm by a doctor, nurse or pharmacist.

An initial dose of COMIRNATY Original/Omicron BA.4-5 may be given as a booster at
least 3 months after the primary vaccination for people 12 years of age and older.

A doctor, nurse or pharmacist will observe you for at least 15 minutes after being
given COMIRNATY Original/Omicron BA.4-5.

COMIRNATY Original/Omicron BA.4-5 is only given as booster doses. For primary vaccination,
ask your doctor or pharmacist.

What should I know while being given COMIRNATY Original/Omicron BA.4-5?

Things you should know

An initial dose of COMIRNATY Original/Omicron BA.4-5 may be given as a booster at
least 3 months after the primary vaccination for people 12 years of age and older.

COMIRNATY Original/Omicron BA.4-5 may also be given to individuals 12 years of age
and older at least 3 months after a previous booster dose of any COVID 19 vaccine.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how COMIRNATY
Original/Omicron BA.4-5 affects you.

Some of the side effects of COMIRNATY Original/Omicron BA.4-5 may temporarily affect
your ability to drive or use machines.

Storage of the vaccine

A doctor, nurse or pharmacist will prepare the injection for you before you are given
it.

Getting rid of any unwanted vaccine

A doctor, nurse or pharmacist will dispose of any unused vaccine.

Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of
them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you
have any further questions about side effects.

Other side effects (frequency unknown)

Tell your doctor or pharmacist if you notice anything else that may be making you
feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can
report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems . By reporting side effects, you can help provide more information on the safety of
this vaccine.

Product details

What COMIRNATY Original/Omicron BA.4-5 contains

Active ingredients

(main ingredients)

Tozinameran

Famtozinameran

Other ingredients

(inactive ingredients)

((4-hydroxybutyl)azanediyl) bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC-0315)

2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide (ALC-0159)

Distearoylphosphatidylcholine (DSPC)

Cholesterol

Sucrose

Trometamol

Trometamol hydrochloride

Water for injections

Do not receive this vaccine if you are allergic to any of these ingredients.

What COMIRNATY Original/Omicron BA.4-5 looks like

COMIRNATY Original/Omicron BA.4-5 is a white to off-white suspension.

COMIRNATY Original/Omicron BA.4-5 is provided in packs of 10 and 195 in multidose
clear glass vials with grey flip-off caps. Each dose is 0.3 mL and each vial contains
6 doses of vaccine (2.25 mL fill).

AUST R 400874.

Not all presentations may be available.

Who distributes COMIRNATY Original/Omicron BA.4-5

Pfizer Australia Pty Ltd

Sydney NSW

Toll Free Number: 1800 675 229

COMIRNATY® is a registered trademark of BioNTech SE. Used under license.

This leaflet was prepared in January 2023.

© Copyright

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Cystic Fibrosis Pipeline Appears Robust With 75+ Key Pharma

DelveInsight's, "Cystic Fibrosis Pipeline Insight, 2022," report provides comprehensive insights about 75+ companies and 80+ pipeline drugs in the Cystic Fibrosis pipeline landscape. It covers the Cystic Fibrosis pipeline drug profiles, including Cystic Fibrosis clinical trials and nonclinical stage products. It also covers the Cystic Fibrosis pipeline therapeutics assessment by product type, stage, route of administration, and molecule type. It further highlights the inactive pipeline products in this space.
In the Cystic Fibrosis pipeline report, detailed description of the drug is given which includes mechanism of action of the drug, clinical studies, Cystic Fibrosis NDA approvals (if any), and product development activities comprising the technology, Cystic Fibrosis collaborations, licensing, mergers and acquisition, funding, designations and other product related details.

Key takeaways from the Cystic Fibrosis Pipeline Insight Report

• DelveInsight's Cystic Fibrosis Pipeline report depicts a robust space with 75+ active players working to develop 80+ pipeline therapies for Cystic Fibrosis.

• The leading Cystic Fibrosis Companies such as Eloxx Pharmaceuticals, NovaBiotics, Arrowhead Pharmaceuticals, SolAeroMed, Translate Bio, Inc., Path BioAnalytics, Aridis Pharmaceuticals, Vertex Pharmaceuticals, AlgiPharma, Corbus Pharmaceuticals, Galapagos NV, Santhera Pharmaceuticals, Calithera Biosciences, Inc, AbbVie, Spyryx Biosciences, Inc., Verona Pharma, Laurent Pharmaceuticals Inc., Ligand Pharmaceuticals, Boehringer Ingelheim, OrPro Therapeutics, Protalix Biotherapeutics, Krystal Biotech, Insmed Incorporated, BiomX, Arcturus Therapeutics, and others are developing potential drug candidates to improve the Cystic Fibrosis treatment scenario.

• Promising Cystic Fibrosis Pipeline Therapies such as OligoG, Ensifentrine, MRT5005, CB280, KB407, SPL84231, and others

• The Cystic Fibrosis companies and academics are working to assess challenges and seek opportunities that could influence Cystic Fibrosis R&D. The therapies under development are focused on novel approaches to treat/improve Cystic Fibrosis.

Request a sample and discover the recent advances in Cystic Fibrosis treatment and click here for Cystic Fibrosis Pipeline Report @ www.delveinsight.com/sample-request/cystic-fibrosis-pipeline?utm_source=openpr&utm_medium=pressrelease&utm_campaign=ypr

Cystic Fibrosis Overview
Cystic fibrosis is a progressive, genetic disease that causes long-lasting lung infections and limits the ability to breathe over time. More than 30,000 children and adults in the United States have CF (70,000 worldwide) and CF affects people of every racial and ethnic group. In people with CF, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the CFTR protein to become dysfunctional.

Recent Breakthroughs of Cystic Fibrosis Treatment Landscape

• In December 2021, AlgiPharma has been awarded up to NOK 16 million from the Norwegian Research Councils Innovation Project for the Industrial Sector program for the project "Therapeutic Alginates for Resistant and Recurrent Infections: Generating Eradication Therapies (TARRGET)". The project grant awarded from the Research Council combined with the Norwegian government tax incentive scheme (SkatteFUNN) results in a total award value for AlgiPharma of about NOK 22 million (about EUR 2.2 MM / USD 2.5 MM).

• AlgiPharma has received more than USD 46 million in research and development grants from EU's 7th framework program, Horizon 2020, and Eurostars programs, the Norwegian Research Council, Innovate UK, US Army through Congressional Earmark funding, and the Cystic Fibrosis Foundation (CFF).

• In November 2021, Calithera Biosciences shared interim safety and efficacy results from a Phase 1b, randomized, double-blind, placebo-controlled, dose-escalation trial evaluating CB-280, the company's investigational arginase inhibitor, in adults with cystic fibrosis (CF). The data were shared in a poster presentation at the North American Cystic Fibrosis Foundation Conference (NACFC; Abstract 529).CB-280 demonstrated linear pharmacokinetics with plasma exposure increasing proportionally with dose. Complete and continuous target inhibition in plasma was achieved at the 100 mg dose and above. CB-280 also demonstrated robust pharmacodynamic effects, with rapid and significant dose-proportional increases in plasma arginine, the key driver of NO production.

• In November 2021, Eloxx Pharmaceuticals announced positive topline results from the monotherapy arms of its Phase 2 clinical trial of ELX-02 in Class 1 cystic fibrosis (CF) patients with at least one G542X nonsense allele mutation. ELX-02 was well tolerated and achieved a statistically significant 5.4mmol/L reduction in sweat chloride in patients at the1.5mg/kg/day dose.

• In October 2021, Boehringer Ingelheim, IP Group, the UK Cystic Fibrosis Gene Therapy Consortium (GTC, consisting of researchers from Imperial College London and the Universities of Oxford and Edinburgh) and Oxford Biomedica (OXB), today that Boehringer Ingelheim has exercised its options on intellectual property and know-how from the partners to progress and further accelerate the development of a potential, new treatment option for patients with CF. In the partnership, IP Group, acting on behalf of the three GTC host Universities, is granting exclusive global rights to develop, manufacture, register, and commercialize this lentiviral vector-based gene therapy for the treatment of cystic fibrosis. The GTC is additionally contributing its knowledge in pre-clinical research and clinical gene therapy development. OXB is adding its leading competence in manufacturing lentiviral vector-based therapies to Boehringer Ingelheim's expertise in the development of novel breakthrough therapies for respiratory diseases.

• In August 2021, Sanofi entered into a definitive agreement with Translate Bio (NASDAQ: TBIO), a clinical-stage mRNA therapeutics company, under which Sanofi will acquire all outstanding shares of Translate Bio for $38.00 per share in cash, which represents a total equity value of approximately $3.2 billion (on a fully diluted basis). The Sanofi and Translate Bio Boards of Directors unanimously approved the transaction.On the therapeutic side, Translate Bio has an early-stage pipeline in cystic fibrosis and other rare pulmonary diseases. In addition, discovery work is ongoing in diseases that affect the liver, and Translate Bio's MRTTM platform may be applied to various classes of treatments, such as therapeutic antibodies or vaccines in areas such as oncology. Sanofi's recent acquisition of Tidal Therapeutics expanded the company's mRNA research capabilities in both immuno-oncology and inflammatory diseases. The Translate Bio acquisition further accelerates Sanofi's efforts to develop transformative medicines using mRNA technology.

• In August 2019, Path BioAnalytics Inc. (PBA) announced it had licensed rights to cavosonstat from Laurel Therapeutics. Cavosonstat is a novel CFTR modulator designed to correct a subset of CFTR mutations by increasing stability of the CFTR protein in the cell membrane through inhibition of S-nitrosoglutathione reductase (GSNOR) and preservation of S-nitrosoglutathione (GSNO).

Request a sample and discover the recent advances in Cystic Fibrosis Pipeline Therapies, visit Cystic Fibrosis Treatment Landscape @ www.delveinsight.com/sample-request/cystic-fibrosis-pipeline?utm_source=openpr&utm_medium=pressrelease&utm_campaign=ypr

Cystic Fibrosis Emerging Drugs Profile

• ELX-02: Eloxx Pharmaceuticals
ELX-02, is a eukaryotic ribosomal selective glycoside (ERSG) designed to increase the read-through activity in patients with nonsense mutations and enable the production of sufficient amounts of full-length functional protein to restore activity. It is currently in phase II stage of development to treat Cystic fibrosis.Eloxx has also begun evaluation of inhaled (nebulizer-based) delivery of the current subcutaneous formulation of ELX-02. Eloxx believes that inhaled delivery has the potential to further improve the activity of ELX-02 as a single agent and in combination with other drugs given potential for increased drug exposure in the lung versus plasma. Prior animal studies have shown a 19-fold increase in ELX-02 exposure at a similar dose when administered as an inhalation agent versus subcutaneously. We expect to submit an Investigational New Drug application in the second half of 2022.

• S1226: SolAeroMed
S1226 is SolAeroMed's lead therapy. S1226 is formulated to rapidly reopen constricted, mucus plugged airways, and should increase the effectiveness of respiratory drug delivery. The S1226 formulation consists of aerosolized carbon dioxide (CO2) and nebulized perflubron; which is delivered into the lung. The delivery of this formulation results in an immediate relaxant effect on the patient's constricted airways, supported by a lowering of surface tension in inflamed areas (resulting in enhanced bronchial dilation) and possible clearing of mucus plugs of blocked airways.SolAeroMed has completed a phase I trial demonstrating S1226 is safe in healthy subjects and a phase II clinical trial showing S1226 is safe and effective in relieving an allergen-induced asthma. SolAeroMed is currently conducting a phase II clinical trial in cystic fibrosis.

• Lenabasum: Corbus Pharmaceuticals
Lenabasum is a novel, oral, small molecule that selectively binds as an agonist to the receptor type 2 (CB2) and resolves inflammation and limits fibrosis in animal and human models of disease. CB2 is preferentially expressed on activated immune cells and on fibroblasts, muscle cells, and endothelial cells. Lenabasum has demonstrated acceptable safety and tolerability profiles and has not been immunosuppressive in clinical studies to date.CF-002 was a multinational Phase 2b study evaluating the efficacy and safety of lenabasum in CF. This was a double-blind, randomized, placebo-controlled study, with dosing of lenabasum at 5 mg twice per day, lenabasum 20 mg twice per day or placebo twice per day for 28 weeks, with 4 weeks safety follow-up off active treatment. The primary efficacy endpoint was the event rate of new PEx per subject per 28 weeks, when the primary definition of new PEx was physician diagnosis of PEx, prescription of new antibiotics for that PEx starting more than 28 days after completion of the last antibiotic course for any previous PEx, with 4 out of 12 Fuch's criteria present in the subject. The Phase 2b CF study was funded in part by a Therapeutic Development Award for up to $25 Million from the Cystic Fibrosis Foundation.

• Lonodelestat: Santhera Pharmaceuticals
Lonodelestat (previously known as POL6014), a highly potent and selective peptide inhibitor of human neutrophil elastase (hNE), is in development for the treatment of cystic fibrosis. Currently, it is in Phase I/II stage of development. Santhera obtained the worldwide, exclusive rights from Polyphor AG to develop and commercialize lonodelestat in CF and other diseases. In preclinical studies lonodelestat was effective in animal models of neutrophil activation in lung tissue and of acute lung injury (ALI). Currently available clinical data demonstrated that single and multiple doses (Phase 1b) of lonodelestat when administered by inhalation via an optimized eFlow® nebulizer (PARI Pharma GmbH) can lead to high drug concentrations within the lung, resulting in inhibition of hNE in sputum of patients, an enzyme associated with lung tissue inflammation. The Phase 1b study further confirmed the tolerability of lonodelestat after treatment of up to four weeks in patients with CF. Lonodelestat may also show therapeutic benefit for a range of neutrophilic pulmonary diseases with high medical need such as non-CF bronchiectasis (NCFB), alpha-1 antitrypsin deficiency (AATD), chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) or primary ciliary dyskinesia (PCD). Lonodelestat has EU orphan drug designations (ODD) for the treatment of CF as well as for AATD and PCD in both the EU and US.

DelveInsight's Cystic Fibrosis Pipeline Report covers around 80+ products under different phases of clinical development like
• Late stage products (Phase III)
• Mid-stage products (Phase II)
• Early-stage product (Phase I) along with the details of
• Pre-clinical and Discovery stage candidates
• Discontinued & Inactive candidates
• Route of Administration

Get to know more information about the Cystic Fibrosis Emerging Drugs and Cystic Fibrosis Companies of the report @ www.delveinsight.com/sample-request/cystic-fibrosis-pipeline?utm_source=openpr&utm_medium=pressrelease&utm_campaign=ypr

Scope of the Cystic Fibrosis Pipeline Report
• Coverage- Global
• Cystic Fibrosis Pipeline Segmentation: Product Type, Molecule Type, Mechanism of Action, Route of Action
• Cystic Fibrosis Companies- Eloxx Pharmaceuticals, NovaBiotics, Arrowhead Pharmaceuticals, SolAeroMed, Translate Bio, Inc., Path BioAnalytics, Aridis Pharmaceuticals, Vertex Pharmaceuticals, AlgiPharma, Corbus Pharmaceuticals, Galapagos NV, Santhera Pharmaceuticals, Calithera Biosciences, Inc, AbbVie, Spyryx Biosciences, Inc., Verona Pharma, Laurent Pharmaceuticals Inc., Ligand Pharmaceuticals, Boehringer Ingelheim, OrPro Therapeutics, Protalix Biotherapeutics, Krystal Biotech, Insmed Incorporated, BiomX, Arcturus Therapeutics, and others
• Cystic Fibrosis Therapies- OligoG, Ensifentrine, MRT5005, CB280, KB407, SPL84231, and others

Dive deep into rich insights for drugs for Cystic Fibrosis Market Drivers and Cystic Fibrosis Market Barriers, click here Cystic Fibrosis Unmet Needs and Analyst Views @ www.delveinsight.com/sample-request/cystic-fibrosis-pipeline?utm_source=openpr&utm_medium=pressrelease&utm_campaign=ypr

Table of content
1. Introduction
2. Executive Summary
3. Cystic Fibrosis: Overview
4. Pipeline Therapeutics
5. Therapeutic Assessment
6. Cystic Fibrosis - DelveInsight's Analytical Perspective
7. Late Stage Products (Phase III)
8. Drug name: Company Name
9. Mid Stage Products (Phase II)
10. OligoG : Algi pharma
11. Early Stage Products (Phase I)
12. CB280:Calithera Biosciences
13. Preclinical and Discovery Stage Products
14. SPL84231: Spli Sense
15. Inactive Products
16. Cystic Fibrosis -Key Companies
17. Cystic Fibrosis -Key Products
18. Cystic Fibrosis - Unmet Needs
19. Cystic Fibrosis - Market Drivers and Barriers
20. Cystic Fibrosis - Future Perspectives and Conclusion
21. Cystic Fibrosis -Analyst Views
22. Cystic Fibrosis- Key Companies
23. Appendix

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Each year, as flu season peaks, medical professionals who take care of pregnant women have to gear up to combat misinformation around the influenza vaccine.

"We've always seen fear or distrust of not wanting to get a flu vaccine in pregnancy," Melissa Simon, an obstetrician gynecologist at Northwestern Medicine, told Salon. "Every year we have to be very consistent and start that very clear, consistent messaging that the flu vaccine is indeed very well studied in pregnancy, it's very safe in pregnancy, and it actually improves outcomes."

As Simon alluded to, a 2018 study published in Clinical Infectious Diseases examined the influenza's vaccine effectiveness and flu-related hospitalizations in pregnant women between 2010 and 2016. The researchers concluded that getting vaccinated reduced a person's risk of being hospitalized by 40 percent. A separate study published in 2013 estimated that a pregnant woman's risk of getting a flu-related acute respiratory infection by one-half. Indeed, research has shown that pregnant women have a higher risk of getting hospitalized with pneumonia or being admitted to the intensive care unit when being unvaccinated and having the flu.

"When you have the flu, your lungs have a harder time to breathe [in pregnancy]," Simon said. "And you need those lungs to breathe well, in order to help give oxygen to your baby."

Denise Jamieson, professor and chair of the Department of Gynecology & Obstetrics ast Emory University School of Medicine, told Salon via email that there have often been long-standing myths and misconceptions about the flu vaccine that she's seen in her patients.

"Although the flu vaccine has been recommended in pregnancy for many decades, only about half of pregnant persons are vaccinated for flu each year," Jamieson said. "I have heard many pregnant persons say 'Whenever I get the flu vaccine I get sick, so I am not getting it while I am pregnant".'"

Jamieson said the influenza vaccine can cause mild side effects, but it's not true that it makes a person sick with the flu.

"In addition, there are many long and strongly held beliefs about the flu vaccine in families and communities," Jamieson said. "For example, my patients will say 'My mother never got vaccinated and she told me not to get vaccinated, particularly not in pregnancy.'"

Despite research and recommendations ensuring the safety of vaccines in pregnancy, if you search "flu shot" in many online pregnancy groups, you will find plenty of pregnant women expressing hesitancy at the thought of getting vaccinated. And it's not just the flu shot. When the COVID-19 vaccine finally came to exist, online pregnancy forums were immediately fraught with misinformation about these vaccines' safety. A Kaiser Family Foundation's COVID-19 Vaccine Monitor published over the summer found that nearly three-quarters of women who were pregnant or trying to conceive either believed or were unsure about at least one of the COVID-19 vaccine myths asked in the survey.

"More than two years into the pandemic, there's a surprising amount of confusion about the vaccine's safety for pregnant women," Mollyann Brodie, a Kaiser Family Foundation Executive Vice President, said in a statement at the time. "The fact that so many younger women incorrectly believe the vaccines can cause infertility or that they're not safe for pregnant women highlights the real challenges facing public health officials."

It's a question medical professionals have long been fixated on: why is health and vaccine misinformation so common in online pregnancy groups that are meant to provide support? Why does misinformation prevail when the research has advanced?

"Disinformation runs rampant on online forums because there's no one checking," Simon postulated. "There's no accountability, and no one's editing."

Andrea Vincent, an admin for a Facebook pregnancy support group, told Salon as admins they often find themselves having to monitor misinformation in the group.


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"We've always had a lot of rules and they've had to increase in the last few years with the world changing," Vincent said. "But I think that's helped us keep misinformation out and we really try to keep talking a lot behind the scenes about what we allow and what we don't."

Vincent said she believes that people seek out medical advice in online support groups, instead of asking their medical providers, for a couple of reasons. 

"I think people want reassurance that it's normal, so they don't have to go to their doctor or they think it's easier to go to a group, or sometimes people have gone to a doctor and want to then ask the group, 'this is what my doctor says, has anyone done this?'" Vincent said. "There's a lot of misinformation out there, and it's scary to have a baby."

Previously, Simon told Salon the fact that a lot of the misinformation clouds pregnancy stems from "structural issues," such as "excluding pregnant and birthing and lactating persons" from research. "And that's really unfortunate because when certain groups are left behind from being included in clinical trials, there is relatively less data." But now, more data is here. 

Jamieson told Salon she believes there is often a reluctance to do anything in pregnancy, like take medications or vaccines, in a misguided attempt to ensure that they've done everything to ensure their babies are born healthy. But this can often have the reverse effect.

"What is not appreciated is that by doing nothing, and not getting vaccinated, the risks to the mother and baby can be substantial," Jamieson said. "Pregnant people who are vaccinated for influenza can also pass protective antibodies to the fetus; these protective antibodies are critically important because they help protect newborn babies, who are too young to be vaccinated, from getting sick with influenza."

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Millions of Americans of all ages suffer from post-COVID-19 condition, or long COVID. In fact, recent data show that the condition is affecting more than 16 million working-age Americans and is keeping between two and four million of them out of work completely.

According to the World Health Organization, long COVID occurs when an individual continues to suffer from prolonged symptoms of the virus at least 3 months after initial onset. Common symptoms include difficulty thinking or concentrating, sleep trouble, dizziness, headaches, fatigue, brain fog and more. In many cases, these symptoms prove to be debilitating and result in significant health and quality of life issues.

Health care professionals around the globe are working tirelessly to understand, diagnose. and treat long COVID. While there is no single treatment that has been approved to completely rid those with long COVID of their symptoms, a growing body of clinical research supports the potential of a specific hyperbaric oxygen therapy (HBOT) protocol to become part of the standard of care for the condition. A breakthrough randomized controlled trial on use of the protocol for symptom management was published in Scientific Reports in July.

The study was conducted by the Sagol Center for Hyperbaric Medicine and Research at Shamir Medical Center in Israel, known for its pioneering research on novel indications of hyperbaric medicine for cognitive and physical rehabilitation. The cohort was comprised of 73 participants with reported long COVID cognitive symptoms. To study the effectiveness of the HBOT protocol in treating these individuals, patients were randomly assigned to either a treatment or placebo (sham) group. The unique treatment protocol was comprised of 40 daily HBOT sessions, 5 sessions per week.

The randomized, double-blind, placebo-controlled clinical trial demonstrated that HBOT, when used in a specific protocol was effective at improving symptoms of long COVID. Participants showed significant improvement in global cognitive function, energy, sleep, psychiatric symptoms, and pain interference. Participants in the control group did not exhibit these same improvements.

The study revealed that HBOT can induce structural and functional repair of damaged regions of the brain and improve cognitive, behavioral, and emotional function of patients with long COVID conditions.

Further analysis of the brain network activity of those patients was published in the journal Neuroimage: Clinical and shed additionallight on how COVID can disrupt the normal functionality of the brain. Moreover, the study shows that in post-COVID-19 patients, HBOT improves disruptions observed in white matter tracts (neuronal fibers) and alters the functional connectivity organization of neural pathways attributed to cognitive and emotional recovery.

While HBOT has been used for centuries, this new study indicates that utilizing a specific protocol involving oxygen fluctuation in a multiplace chamber can induce neurogenesis, neuronal stem cell proliferation, increased blood flow, and neuroplasticity. HBOT involves breathing 100% pure oxygen while in a controlled hyperbaric chamber. The air pressure inside is elevated above normal to help the lungs collect more oxygen and more effectively deliver that oxygen to damaged tissues, thus expediting the healing process. Deliberate fluctuations of oxygen levels during each HBOT session work to induce the hypoxia inducible factor, increasing vascularization and promoting angiogenesis in damaged brain tissues.

The specific HBOT protocol studied here is in use for treatment of the symptoms of long COVID at Aviv Clinics through an exclusive partnership with the Sagol Center. The partnership allows Aviv clinics in Florida and Dubai to use the protocols, evaluation methods, and treatments used in the Scientific Reports study. Patient assessment includes high resolution brain imaging to identify damage in the brain caused by the SARS-CoV-2 virus. When combined with the results of intensive cognitive, physical, and nutritional assessments, these scans allow a multidisciplinary team of clinicians to develop a customized treatment program to help each patient.


Shai Efrati, MD, is founder and director of the Sagol Center for Hyperbaric Medicine and Research at Shamir Medical Center, Be'er Ya'akov, Israel, where he also serves as director of research and development and head of nephrology. Efrati’s research focuses on novel aspects of hyperbaric medicine and brain rehabilitation. He is a professor at the Sackler School of Medicine and the Sagol School of Neuroscience in Tel Aviv University. Since 2008, he has served as Chairman of the Israeli Society for Diving and Hyperbaric Medicine.


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Study setting

This study is a prospective, parallel-group randomized, controlled, exploratory clinical trial. Participants will be recruited from the Guangdong Provincial Hospital of Chinese Medicine Clinic. They are outpatients attending a clinic or inpatients being discharged home and evaluated by two experienced respiratory physicians. Patients are invited to meet with the research physicians to discuss any remaining questions and sign the informed consent. Thereafter, the participants are randomly assigned to either the trial or control group as a ratio of 1:1. The trial group will receive PR integrated with coached exercise training. The control group will receive a traditional PR program. Owing to the exercise intervention, it is not possible to blind participants or those involved in the provision of care. However, the researchers collecting primary data and performing statistical analyses will be blinded to the allocation. The design is open label with only outcome assessors and data analysts being blinded, so unblinding will not occur. The study design is shown in Fig. 1.

Fig. 1
figure 1

Flow chart describing study design

Eligibility criteria

We will include participants aged between 40 and 80 years, diagnosed with COPD (a post-bronchodilator FEV1 < 70% and < 80% of predicted normal values), who are clinically stable, have not experienced an acute exacerbation for at least 4 weeks before the trial, do not participate in systematic exercise training in the past 6 months, and have a 6-min walk test (6MWT) distance between 350 and 550 m.

We will exclude participants with severe comorbidities, including coronary heart disease, arterial aneurysm, severe hepatic and renal dysfunction, and uncontrolled hypertension. Patients with mental diseases, deafness, limb activity disorder, and inability to cooperate are also excluded from the trial.

Patients can leave the study at any time for any reason. Intervention can also be ended by the investigators if the patient is uncooperative and does not attend study visits. This study will be ended in case of any abundance in adverse events or procedure-related complications.

Randomization

A list of random numbers is generated using IBM SPSS statistical software (version 23.0). Hence, every participant will match a number and the information is blind to other trialists. Opaque envelopes containing a number are used to randomly assign participants to either the trial or control group. Two trialists will generate the allocation sequence and assign participants to interventions together.

Sample size calculation

For the primary outcome, a change of 25 m in the 6-MWT distance is considered to be the minimal important difference (MID) in patients with COPD [16], based on a two-sample independent t-test with a given MID of 25 m, standard deviation of 44.6 m, power of 80%, and significance level of 0.05 [17]. Accordingly, the calculated sample size of each group is 50. Assuming a dropout rate of 15% resulted in 18 patients being included in the final study population.

Interventions

After baseline data collection, the patients will be randomly divided into the trial or control group. Participants in both the groups will receive usual care, and PR included health education, nutrition guidance, psychological support, and exercise training [6, 18]. The intervention will be performed three times per week for 12 consecutive weeks. The only difference in intervention between both groups is the exercise training.

In the control group, exercise sessions, which mostly included walking and swimming, lasted for at least 30 min, three times a week, with a weekly follow-up. In contrast, patients in the trial group will receive exercise training guided by a sports coach, which lasts for 60 min, once a week at the hospital, and for 30 min, twice a week at home, conducted through a video. Exercise training for the trial group consists of warm-up exercise, aerobic exercise, resistance exercise, respiratory rhythm adjustment, and respiratory muscle training.

Warm-up exercise

Warm-up exercise is based on Baduanjin combined with lip-constricted breathing and abdominal breathing. Baduanjin is a traditional Chinese physical exercise that involves mild exercise and respiratory regulation [19].

Aerobic exercise

Considering the tolerance of patients with COPD, sports coaches integrate aerobic exercise into a set of aerobics. Aerobics include eight movements and could be performed in the standing or sitting position according to the patient’s condition. Each movement is performed in 4–6 sets of 8–16 repetitions. Between each set, there is a break of 10 s. If the patient is unable to tolerate the exercise, the break time could be extended.

Resistance training

Resistance training could also be performed while standing or sitting. The sports coach integrates resistance exercises into a set of aerobics, including eight movements with a stretch belt (1.5 m, 22 pounds). Each movement consists of 4–6 sets of 8–16 repetitions. Between each set, there is a break for 10 s. If the patient is unable to keep up, the break time will be extended.

Respiratory muscle training

Patients receive respiratory muscle training through abdominal breathing, wherein the abdomen gently puffed-up during inhalation and sank during exhalation. A sandbag weighing 5 kg will be placed on the abdomen, followed by abdominal breathing for 3 min.

Respiratory rhythm adjustment

Patients breath is through the nose and breath out through the mouth slowly. Respiratory rhythm adjustment runs through the training.

In both groups, each patient has an exercise log, which is completed by a supervisor who instructed the sessions online. The exercise log contains adverse events, completed exercises, and a record of vital signs before and after exercise.

Outcome measures and follow-up

Data on the outcomes will be collected at baseline and after 12 weeks. Patients are followed up weekly in the outpatient department or through online methods, including telephone and WeChat. The primary outcome measure is exercise tolerance using the 6-MWT. Secondary outcomes are the peak oxygen uptake (V̇O2) of cardiopulmonary exercise tests, the COPD Assessment Test (CAT), and the St. Georges Respiratory Questionnaire (SGRQ). Other outcomes include changes in postbronchodilator forced expiratory volume at 1st second (FEV1), forced vital capacity (FVC), body fat and muscle composition, mental status measured using the Hamilton rating scale for depression scores (HAMD-24) and the Hamilton Anxiety rating scale (HAMA).

The investigator will inquire about the occurrence of adverse events. The details of every adverse event will be reported in the case report form (CRF). The same investigator will record all outcome measures to maintain standardization in the procedure.

Measurements

6-min walking test

This test measures the distance a participant can walk in 6 min. The patients will be instructed to walk as far as possible in 6 min and receive recommended standardized encouragement. Two tests will be performed on each occasion, and the best distance is recorded. A 30-min rest will be mandatory between the first and second 6-MWT [20, 21].

Peak oxygen uptake of cardiopulmonary exercise tests

Cardiopulmonary exercise testing (CPET) will start with an initial rest of 3 min, followed by unloaded cycling for 3 min and a subsequent increment of 5–15 W after each minute. The aim is achieving a total exercise performance time of 8 to 12 min. Patients are asked to maintain a pedaling frequency of 50–60 rpm on a cycle ergometer (SCHILLER CS-200 Ergo- Spiro, Switzerland). If the patients display symptoms such as unsustainable dyspnea or leg fatigue, chest pain, ECG-significant ST-segment depression, and a drop in systolic blood pressure or oxygen saturation (SpO2) ≤ 84%, the test will be stopped. V̇O2 will be recorded as the mean value of VO2 during the last 20 s of the test. VO2 will be expressed both as an absolute value (l/min) and in terms of mL/kg/min [22, 23].

COPD Assessment Test (CAT)

CAT is a patient completes an 8-item questionnaire that assesses the impact of COPD on self-reported health status and symptoms [24]. Each item is scored from 0 to 5 points (0 indicating no impact or symptoms and 5 indicating the worst possible impact or symptoms) summing up to a total CAT score in the range of 0–40 points.

St. Georges Respiratory Questionnaire

The SGRQ is a self-administered questionnaire designed to measure self-perceived impairments in health and quality of life in individuals with airway diseases [25]. The three component scores of the questionnaire, including symptoms, activity, and impact (on daily life) were calculated, giving a total score between 0 and 100, wherein 0 indicates good health and 100 indicates very poor health.

Pulmonary function testing

Pulmonary function tests are performed by spirometry using the same machine and the same technician for all patients according to international recommendations [26, 27]. A flow-sensing spirometer and a body plethysmograph connected to a computer (Master Screen Diffusion Combined Pulmonary Function Tester, Jaeger, Germany) will be used for the measurements.

Body fat and muscle composition

Body fat and muscle composition will be measured using multifrequency bioelectrical impedance analysis (BIA) via a body composition analyzer (InBody 770, Biospace Co Ltd, Seoul, South Korea). The participant stands barefoot on the platform of the device with the soles of their feet on the electrodes. The participants then grasp the handles of the unit with their thumb and fingers to maintain direct contact with the electrodes and stood still for 1 min while maintaining their elbows at full extension and shoulder joints abducted to approximately 30° angle. During the assessment, BIA analyzers introduce a small electrical current into the body and measure the resistance or impedance to the current flow to calculate skeletal muscle, fat content, and other components of the body. Data on total body composition, body fat percentage, muscle mass, and bone mass will also be collected.

Hamilton Rating Scale for Depression (HAMD-24) and Hamilton Anxiety rating (HAMA) scales

HAMD-24 and HAMA are used to evaluate depression and anxiety levels of participants [28]. The HAMD scale includes 24 problem items, which can be classified into seven-factor structures: anxiety/somatization, body mass, cognitive impairment, day-night change, block, sleep disturbance, and sense of hopelessness. A total score of ≥ 8 indicates that the patient has positive depressive symptoms. The HAMA scale contains 14 items, most of which can be scored on a 0–4 scale.

Participant timeline

The study will last for 3 years. Recruitment of patients started in March 2021. Baseline information including sex, age, body mass index, and history of smoking will be collected at the beginning. Vital signs including blood pressure, heart rate, oxygen saturation, and respiratory rate are collected every week during the period of intervention to evaluate safety. Outcome data are collected before intervention and at 12 weeks. The protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 [29]. And A brief SPIRIT flow diagram is shown in Table 1. A populated SPIRIT checklist is provided in Additional file.

Table 1 Tabulated summary of the study schedule

Adverse event reporting

Adverse events will be recorded in CRF (Case Report Form). Serious adverse events will be reported within 24 h to the principal investigation and Institutional Review Board. The steering committee consists of a pulmonologist and a respiratory nurse who will survey the study procedure and evaluate serious adverse events. The steering group is the trialists of this study. If there is any damage related to the study, the research group will pay the medical expenses and make corresponding financial compensation according to laws and regulations.

Data management and statistical analysis

Researchers will make appointments for the next follow-up to promote participant retention. Data will be collected in the CRF on paper by the same investigator. All the CRF on paper will be stored in a locked cabinet. Access to the data sets is only available to the investigators in this study. Incomplete data of patients who are lost to follow-up for various reasons will be eliminated. Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine makes a visit per year and checks the presence and completeness of the investigation file. All substantial amendments will be notified to the Committee, and non-substantial amendments will be recorded.

Outcome measures will be analyzed using a t-test at the end of the trial. IBM SPSS statistical software for Windows (Version 23.0) is used to analyze the data for the outcome measures. Data is presented as the mean and standard deviation.

Dissemination

Results of this research will be disclosed completely in international peer-reviewed journals. Both positive and negative results will be reported.

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There’s a respiratory virus making headlines this year that you’ve likely already had at some point in life. Nonetheless, it’s posing a threat to seniors. Respiratory syncytial virus, known as RSV, resembles the common cold. While most healthy adults and children get better within a couple weeks, the virus, which infects the nose, throat, lungs, and breathing passages of the upper and lower respiratory system, is very dangerous for babies under 6 months and adults 65 and older. Each year in the United States, 60,000 to 120,000 adults over age 65 and 58,000 to 80,000 children under the age of five are hospitalized. Up to 10,000 adults over age 65 and some 100 to 300 children die from the infection.

“RSV has already peaked in the U.S. this season, but I do think that there will be multiple RSV vaccines available for older adults in time for next season,” notes Dr. Amesh Adalja, an infectious disease expert and senior scholar at the Johns Hopkins Center for Health Security.

Here’s a look at what’s known about the new RSV vaccines for older adults, what’s not and what lies ahead for 2023 to protect against the massive harms the virus causes.

Which drug companies are close to making an approved RSV vaccine?

Right now, RSV vaccine trials from drugmakers are still underway, and once they conclude, they will each need to go through a regulatory review and approval process by the U.S. Food and Drug Administration (FDA).

Moderna

On January 17, 2023, Moderna announced their RSV vaccine was 83.7% effective in preventing RSV with two or more symptoms, in people ages 60 and older, and it was 82.4% effective at preventing lower respiratory tract disease with three or more symptoms. No safety concerns were identified during the phase III clinical trial, which enrolled about 37,000 people across 22 countries. The company plans to publish their data in a peer-reviewed journal and file an application for FDA approval of their vaccine in the first half of 2023.

Pfizer

On December 7, 2022, Pfizer announced the FDA granted priority review to their RSV vaccine for older adults 60 years of age or older. On August 25, 2022, the company released data showing the vaccine was 66.7% effective in preventing lower respiratory tract illness in people 60 and over and 85.7% effective at preventing severe disease. Additionally, Pfizer said there were no safety concerns, and that the vaccine was “well tolerated” among participants in the phase III clinical trial. The FDA is currently reviewing the data in the Biologics License Application (known as the BLA), which is tens of thousands of pages long. They are said to decide on whether the vaccine is ready to be marketed by May 2023. If approved, Pfizer’s RSV vaccine will likely be available by fall 2023 to the public. Pfizer is also developing a RSV vaccine for pregnant women, who would be immunized to protect their newborns after delivery.

GlaxoSmithKline (GSK)

On October 13 2022, GSK reported their RSV vaccine was 94.1% effective against severe RSV in adults age 60 years and older with overall efficacy at 82.6%. The vaccine was well tolerated in phase III clinical trial participants with adverse effects typically mild-to-moderate. An FDA decision on that filing, made by GSK in late 2022, is also expected in May 2023.

How do the new RSV vaccines work?

Different types of vaccines work in different ways to offer protection, but none of the RSV vaccine candidates referenced above are “live vaccines.” 

“One of the 11 proteins the RSV virus uses to infect our healthy cells is called the F glycoprotein,” explains Rob Swanda, who holds his doctorate in biochemistry and is a mRNA biochemist. The mRNA RSV vaccine designed by Moderna “gives our cells the instruction (via mRNA) to make the F glycoprotein ourselves,” says Swanda. This, he says, allows our immune system to recognize that this F glycoprotein is not one of our own proteins, create an immune response against it, and then, keep memory of what that protein looks like.

“It’s like receiving a cooking recipe that can’t be stored or saved,” explains Swanda, who is known for his whiteboard videos explaining vaccine science. “You use your own ingredients to make the dish, then you know what the product tastes like, and if you came across that same dish in the future you would remember that you tried it before.”

Researchers have been studying and working with mRNA vaccines for decades — long before the pandemic and the experience in developing the COVID-19 mRNA vaccine played a major role in getting these RSV vaccines close to the finish line.

What are the side effects?

The majority of side effects associated in the RSV vaccine trials included those, according to Swanda, common with any injection:

  • Pain
  • Fatigue
  • Headaches
  • Muscle pain
  • Joint pain

Marty Davey, 64, a registered dietitian from Yonkers, New York, and her husband, Jim Fitzpatrick, 72, are currently participating in one of the RSV vaccine trials. “We each got an RSV vaccine about six months ago, and so far, so good,” she says.

The couple initially saw an ad on Facebook recruiting seniors in good health to be a part of the two-year drug trial, which is run in their area by Drug Trials America in Hartsdale, New York. “We get a notification every Monday to let the researchers know how we are feeling, if we can work, and if we can do daily living activities, and were given thermometers to record our temperature the first two weeks after receiving the vaccine,” she explains.

Since the RSV vaccine candidates are using the same technology as the mRNA COVID-19 vaccines, Swanda said your health care provider should have appropriate information regarding compatibility of the RSV vaccination and any other medications you may be taking.

“The benefit of the vaccines is in preventing severe diseases for RSV and not of use once someone is already experiencing the disease.”

— DR. AMESH ADALJA, AN INFECTIOUS DISEASE SPECIALIST

Can getting the RSV vaccine eventually help older adults hospitalized with the virus?  

If you or a loved one is hospitalized with RSV, it’s natural to want a magic cure or any kind of relief to help. Unfortunately, it’s not that simple.

There is no medication to treat RSV currently. “The RSV vaccine is a preventative vaccine, not a therapeutic vaccine,” Dr. Adalja points out. In other words, getting it while you’re in the hospital with severe RSV isn’t going to do you any good in terms of treatment. “The benefit of the vaccines is in preventing severe diseases for RSV and not of use once someone is already experiencing the disease,” he explains.

While Davey and Fitzpatrick didn’t report any immediate side effects after receiving their RSV vaccine in the trial, they both came down with COVID-19 at the start of 2023. “You’re bound to come down to something when you’re coming in contact with 300-400 people every day,” says Davey, who takes public transportation to work.

RSV is a different virus than COVID-19, and it is currently unclear if people with long COVID, a chronic condition where people continue to experience symptoms such as fatigue, shortness of breath and brain fog after recovering from COVID-19, are more at risk for RSV compared to those who have fully recovered from COVID-19.

It’s possible respiratory viruses in general (i.e., RSV, COVID-19, flu) may be more prevalent in certain regions or there may be more susceptible people due to increased travel, changes in the viruses themselves or disruptions to the usual preventive measures that were in place during the pandemic.

How to reduce your own and an older loved one’s risk of RSV right now

RSV spreads much more through contaminated surfaces, which makes hand washing and cleaning surfaces more critical. Dr. Adalja also recommends older adults who are high-risk “be cautious in crowded, congregated areas and think about wearing masks in those situations.”

As we age, so too does our immune system. Older adults are more vulnerable to other vaccine-preventable diseases like flu, COVID-19, pneumonia and shingles.

“In my experience, professionally, there are an awful lot of folks who say, ‘I’ll get a pill for that.’ But there are preventative things you could be doing to get healthier and have a better quality of life,” notes Davey. “We all lived through a pandemic and know about long COVID. Once you go on a respirator, your lungs are forever changed. Period.” 

Talk with your own and your senior loved one’s health care provider about risks for diseases and an immunization schedule that is best for you both. 



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For more than two years, scientists have been trying to understand why millions of people across the world are experiencing lingering symptoms despite recovering from their COVID-19 infection. They’ve proposed several hypotheses including the presence of microclots—tiny blood clots that can block capillaries and potentially affect blood and oxygen flow.

In a 2021 study, physiologist Etheresia Pretorius at the Stellenbosch University in South Africa and her colleagues were the first to suggest that microclots may be linked to this debilitating condition called long COVID. In a follow-up study, she and her colleagues showed that the SARS-CoV-2 spike protein triggers the formation of such clots, which the body’s natural clot-busting process doesn’t seem to break down easily.

This finding has led some scientists in the United States, with guidance from Pretorius, to test people with long COVID for microclots. Lisa McCorkell, co-founder of the long COVID-focused Patient-Led Research Collaborative, was thrilled when she heard the news last year.

McCorkell had experienced severe shortness of breath, extreme fatigue, and brain fog for several months following her mild COVID-19 symptoms in March 2020, when the pandemic began. In August that year, when she started to feel better, McCorkell took a workout class. But a day later, her heart rate spiked, she struggled to breathe, and she rushed to the emergency room. “That lowered my baseline quite a bit,” she says. “Before COVID, I was running half marathons, so it was a very dramatic change.”­

In December 2020, the 28-year-old finally came to terms with how sick she was and that her illness wasn’t temporary. In late 2021, her suspicions were confirmed when she was diagnosed with postural orthostatic tachycardia syndrome (POTS), a condition documented in several long COVID patients that can disrupt breathing and cause heart palpitations and dizziness on standing up. POTS has no cure and some patients, including McCorkell, manage symptoms by increasing fluids and salt intake. But a year after her diagnosis she still suffers post-exertional malaise that worsens these symptoms.

What’s frustrating for McCorkell and many other long COVID patients is blood and other routine tests turn up normal despite their debilitating condition. In November 2022, she flew from California to New York where David Putrino, a rehabilitation and long COVID scientist at Mount Sinai Health System, and his collaborators are collecting blood samples to search for microclots. “We’re very early,” Putrino says. “We’ve only tested a few dozen folks so far.” But every sample from long COVID patients, including McCorkell’s, has revealed such clots.

When she first saw the microscope images of fluorescent green blobs revealing the microclots, she cried with relief. For her, the confirmation that she has microclots felt like validation of her illness, “especially after not getting a PCR test at the beginning and being gaslit throughout the last few years.”

While some experts agree the microclots hypothesis is plausible, they think it could be just one piece of the long COVID puzzle. But they want to see more research that demonstrates how these clots contribute to long COVID symptoms and whether getting rid of them leads to improved health outcomes.

How microclots form 

Unlike blood clots that block arteries or veins, microclots occur in small blood vessels. They form when a soluble protein called fibrinogen is exposed to inflammation-causing molecules, which can bind to the fibrinogen and aggregate into sticky blobs. “They are not capable of clogging large vessels; they’re not capable of causing life-threatening symptoms,” Putrino says, but notes, “They can significantly affect organ function.”

Pretorius and her colleagues have been studying such microclots for more than a decade and have observed them in patients with type 2 diabetes, chronic fatigue syndrome, Alzheimer’s, and Parkinson’s disease. In a preliminary 2021 study, they saw substantial microclot formation in the blood of acute COVID-19 patients, as well as people with long COVID who experience persistent symptoms for six months or longer. “The main difference between microclots we find in diabetes and other conditions is that they break up quite easily,” Pretorius says. COVID microclots are harder to disintegrate.

Trapped inside the persistent microclots, her team found high levels of inflammatory molecules and a protein called alpha 2-antiplasmin that prevents their breakdown. Such blockages in tiny blood vessels throughout the body could hinder the supply of oxygen and nutrients to the organs and tissues, potentially leading to long COVID symptoms like fatigue, muscle pain, and brain fog.

But what’s triggering the microclots formation? Pretorius and her colleagues think it’s the SARS-CoV-2 spike protein, which can linger in the blood of long COVID patients for up to a year. In a 2021 study, the team added spike proteins to healthy blood and were able to trigger the development of microclots. They also found that in the presence of the spike, the microclots were more resistant to fibrinolysis—a natural process that enables the removal of clots. “Our belief is that the spike protein binds to the healthy fibrinogen,” Pretorius says. “We think that interaction perhaps makes for a tighter [microclot] structure and a bigger structure.”

If these microclots persist for prolonged periods, the body could produce autoantibodies—proteins that inadvertently attack the body’s own healthy tissues and cause debilitating disorders. “It’s those individuals who we are particularly worried about,” she says.

How scientists detect microclots

Detecting microclots requires a specialized laboratory technique called fluorescence microscopy. “You can’t just go to the doctor’s office and get tested for microclots,” says microbiologist Amy Proal, of the nonprofit PolyBio Research Foundation and co-founder of the long COVID Research Initiative.

The process involves drawing blood, spinning it, and adding a fluorescent agent to see the clots under a fluorescence microscope. It’s not a widely available tool in general pathology labs.

But what’s unknown is the sensitivity and specificity of this method. “If you’ve got 500 long COVID patients, is this assay positive 100 percent of the times or 20 percent,” asks hematologist Jeffery Laurence at the Weill Cornell Medical College in New York City, who isn’t involved in Putrino’s or Pretorius’s research. “Given that a similar phenomenon occurs in other diseases, how specific is this for COVID.”

He also points out that published microclot studies have been done in a small number of long COVID patients, but future work should involve testing blood samples from many more people and replicating the research in several labs. Putrino, in collaboration with immunologist Akiko Iwasaki, at Yale University, plans to test hundreds of long COVID patients “because a few dozens is by no means valid for saying everybody [with long COVID] has microclots,” he says.

For now, Putrino and his team are seeing a correlation between the number of microclots on a microscope slide and the severity of a patient’s cognitive impairment. These include their ability to regulate emotions, plan and put together long-term solutions to problems, or figure out ways to deal with real-time situations as they’re changing. The research team is also developing an objective measure for microclots. “We’re still at a very rudimentary stage,” Putrino says.

Hematologist Yazan Abou-Ismail at the University of Utah, who isn’t associated with the microclots research but finds the theory plausible in the context of long COVID, also hopes to see studies that document what’s happening inside the capillaries and organs of long COVID patients with microclots. “It can be hypothesized that the microclots end up obstructing small blood vessels,” he says, “but we don’t really know whether there’s an actual obstruction.”

Treating microclots

While researchers try to determine the prevalence of microclots in people with long COVID and why they form, patients are suffering and desperate for treatments.

In a December 2021 preprint study, which is yet to peer-reviewed, Pretorius and her team showed a decrease in microclots and reduced platelet activation—a condition that accompanies microclot presence—in 24 long COVID patients who were administered a combination of anticoagulant Apixiban and a dual antiplatelet therapy for a month. However, they’re in the process of revising the study to include more patients and measurements of their health outcomes following the treatment. “But we need clinical trials to show anticoagulation approaches and antiplatelet approaches have efficacy,” Putrino says. He also wonders if clots in small blood vessels may need different anticoagulants compared to those used against large clots.

McCorkell, on the other hand, is taking her treatment into her own hands and experimenting with over-the-counter enzyme supplements like serrapeptas and nattokinase that seem to breakdown blood clots but aren’t approved by the U.S. Food and Drug Administration.

Like many other people with long COVID, McCorkell is disappointed and angered that there aren’t clinical trials to test the use of such supplements and other off-label therapies that some patients are resorting to for relief. Many health providers are also often unable to help. Although she hasn’t experienced any side effects so far, McCorkell knows of some individuals who have had nausea and vomiting episodes from taking the same supplements. Pretorius and her team plan to conduct a study to test if these supplements are effective, but until then many patients are on their own.

“Given the scale of the issue and how much it impacts people’s lives, we need an Operation Warp Speed situation,” McCorkell says. “It’s frustrating that we’re not further along.”



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WEST BEND, Wis.--(BUSINESS WIRE)--
Spaulding Clinical, a full-service Phase I clinical service provider, worked with the U.S. Food and Drug Administration (FDA) to conduct a clinical trial as a part of the FDA’s proactive effort to address the opioid crisis and reduce opioid overdoses and deaths. This trial evaluated whether two common psychotropic drugs would further decrease ventilation when combined with an opioid compared to an opioid alone. Early results indicated that one drug-opioid combination evaluated — paroxetine (an SSRI used to treat depression, anxiety and other conditions) plus oxycodone decreased ventilation compared with oxycodone use alone.

Opioids can decrease ventilatory response to hypercapnia, or excessive carbon dioxide in the bloodstream, which can cause severe respiratory depression or death. Since 2016, the FDA has required boxed warnings for both benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use. Thus, this trial evaluated whether two other psychotropic drug-opioid combinations — paroxetine-oxycodone and quetiapine-oxycodone (compared to oxycodone with a placebo) — would cause similar effects. The results of the trial were published in the October Journal of the American Medical Association.

“Though further investigations are still needed, the early findings of this study — the first to test these combinations in humans — indicate that at least one additional drug used to treat anxiety (paroxetine) could pose similar risks for respiratory depression to those of benzodiazepin­es when either is used in combination with opioids,” said Spaulding Clinical Principal Investigator Jan Matousek, D.O. “While quetiapine combined with oxycodone did not cause this effect, this preliminary study conducted at Spaulding Clinical from January to May 2021 demonstrated that paroxetine combined with oxycodone, versus oxycodone with a placebo, did cause a greater risk of respiratory depression. Further testing is therefore essential to determine if common therapies increase the risk of respiratory depression when combined with opioids.”

Cassandra Erato, Spaulding Clinical CEO, commented, “This study was very complex, requiring extensive training for the breathing procedures and equipment and in-depth monitoring of participants in our intensive care unit, but the Spaulding Clinical research team with the FDA did an incredible job executing. We are proud to partner with the FDA to conduct this critical research that can help contribute to an important, greater effort.”

Further investigation is still needed to ascertain the longer-term effects and determine the clinical relevance of these findings.

About Spaulding Clinical Research

Founded in 2007, Spaulding Clinical is a full-service, state-of-the-art paperless Phase I clinical pharmacology unit. Our facility, originally a hospital, features fully integrated bedside electronic data capture and sets the standard for patient care. We specialize in IND-enabling clinical pharmacology studies, cardiovascular safety, and clinical proof of concept. We provide expertise on study design, offering in-house medical writing, clinical data management, biostatistics, project management, clinical laboratory, and PK/PD analysis. For high-quality data to inform your decisions, Think Spaulding First. To learn more, visit spauldingclinical.com.

Lindsey Langemeier

SCORR Marketing

402-405-4269

[email protected]

Source: Spaulding Clinical



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HOUSTON, Texas (KTRK) -- A recent CDC survey estimated one in 13 American adults have long COVID, meaning they have symptoms three or more months after first contracting the virus.

Long COVID can be debilitating for many sufferers, and now some are turning to a medical treatment plan that hasn't been approved by the FDA, but, according to some doctors, shows promising signs.

Patients enter a hyperbaric oxygen chamber where they will be breathing in pure oxygen in a pressurized space. Imagine oxygen being pushed into places that need it.

SEE ALSO: 80% with long COVID have debilitating conditions: CDC

"Honestly, I was so desperate," patient Amanda Ballenger said with a laugh. "If you had told me to take ayahuasca, I probably would have."

Ballenger believes she got COVID-19 in December 2021. It was mild, but three months later, she was exhausted and weak, unable to even feed herself.

"I can't even explain how bad it was. It was horrific. I would kind of claw myself out of the sofa and to the car to make doctors' appointments, but I wasn't able to even drive myself," she explained. "It was really hard on both of my boys to see their mom like that."

Ballenger says doctors told her she had long haul COVID, but, because the diagnosis is so new, they didn't have many treatments to offer. So, she did exactly what most doctors will tell you not to do. Ballenger started looking online.

She ended up finding a study about hyperbaric oxygen therapy being used to treat long COVID. And when she called the Houston Hyperbaric Oxygen Center, she met Dr. Allison Boyle, a neurologist.

"I'm very opposed to hokey medicine and I'm a pretty big skeptic. I've seen the results for wound care, everybody has," Boyle, who's the center's medical director, said. "You get oxygen delivered to the tissue at risk. It heals...For these other things, we've just seen some amazing cases."

Dr. Boyle and her husband, Brad Copus, bought the Houston Hyperbaric Oxygen Center in October 2020. At first, they mostly treated burns and wounds, which are FDA-approved treatments.

But these days, about a quarter of their patients are coming for long-haul COVID treatment. It's a purpose that isn't FDA-approved, though there are several clinical trials underway.

Oxygen therapy for long COVID is also not covered by insurance. So, each session will cost you $180 to $295. If you need, say, 40 sessions, that'll be around $8,000.

"It's not for everybody. There are some ins and outs that we have to look out for, but at the end of the day, it's not harmful. And if it could potentially get you back to your normal life, I think it's definitely worth looking into," Boyle said.

Ballenger has just finished 40 sessions. She says she started feeling results on her 25th dive, and she's still improving. Today, she says she feels about 90% of her former self.

"Sometimes I still get brain fog. Sometimes I get fatigued, but it's exponentially better than it was earlier in the year," she explained.

"It's really awesome to see this huge bubbly personality out of someone that did not have that when they first walked in," Copus, who is the center's program director, said. "Yes, she's probably our happiest, most cheery patient, too, so it makes our days really fun."

SEE ALSO: Women are more likely than men to develop long COVID, study finds

For more on this story, follow Pooja Lodhia on Facebook,Twitter and Instagram.

Copyright © 2023 KTRK-TV. All Rights Reserved.



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In a recent meta-analysis, published in Advances in Therapy, researchers evaluated the tolerability and safety of SABA short-acting β2-agonist (SABA) reliever monotherapy in adults and adolescents with asthma, noting that SABA overuse may be associated with increased risk of adverse events (AEs).

According to the study’s lead author, Thitiwat Sriprasart, the data showed that mortality was rare with SABA monotherapy, and the rates of serious AEs (SAEs) and discontinuation due to AEs (DAEs) was similar between SABA- and inhaled corticosteroid (ICS)-based treatment groups.

Evaluating SABA Safety in Patients With Asthma

Researchers ultimately analyzed 24 randomized controlled trials published between January 1996 and December 2021. Eligible patients were aged 12 years or older and were treated with fixed-dose or as-needed inhaled SABA reliever monotherapy, ICS monotherapy, or ICS plus long-acting β2-agonist (LABA). The team used fixed-effects models to compare mortality, SAEs, and DAEs between the treatment groups.

The authors reported that 1 death unrelated to treatment was reported in each ICS, ICS plus LABA, and fixed-dose SABA group, with no treatment-related deaths observed. The rates of both SAEs and DAEs were under 4%, according to the authors.

Of note, DAEs were more frequent in the SABA groups compared with ICS groups, which they authors considered may be due to worsening of asthma symptoms being classified as an AE. They noted that SAE risk was comparable between the treatment groups.

Investigators acknowledged the analysis was limited by the publication and reporting bias inherent in literature reviews, as well as a lack of data on individual patient characteristics, particularly in older reports. Authors also noted the long-term effects of SABA use could not be determined given the follow-up duration in the studies.

Overall, “this comprehensive meta-analysis of data available from published clinical trials indicates that treatment with SABA as a reliever therapy does not result in increased mortality or excess SAEs in adult and adolescent patients when used within prescribed limits for symptom relief,” the authors ended.

Read More Reports on the Asthma Resource Center



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In early January, a team of researchers and physicians from Toronto’s Sunnybrook and SickKids hospitals completed the first step in a world-first clinical trial of a new treatment for pediatric brain cancer. They used MRI-guided ultrasound to temporarily open the blood-brain barrier and deliver chemotherapy to a malignant, inoperable brain-stem tumour called diffuse intrinsic pontine glioma, or DIPG, most commonly found in children. Patients currently have an average life expectancy of less than a year after diagnosis. 

The study’s co-principal investigators are James Rutka, a pediatric neurosurgeon at SickKids Hospital who sub-specializes in brain tumour and epilepsy surgery, and Nir Lipsman, a neurosurgeon and director of Sunnybrook’s Harquail Centre for Neuromodulation. Here, they share what happened during the groundbreaking trial: 

Congratulations on this achievement. To start off: what is a diffuse intrinsic pontine glioma?

Rutka: DIPG is the second-most-common malignant brain tumour in children, and primarily affects kids aged five to seven. Typically, patients present with symptoms that can include facial weakness, double vision and ataxia (or incoordination).

What’s the typical outlook for children with this diagnosis?

Rutka: This tumour steadily and rapidly grows within the brain stem. Without treatment, children survive around six months; with treatment, which includes radiation therapy, they might last as long as 18 months. As surgeons, we feel helpless with diagnosis, because there’s nothing we can do surgically to extend life for those who have it. 

That’s shockingly grim. Why is it so difficult to treat?

Lipsman: DIPG is located in the brain stem—the lower part of the brain connected to the spinal cord—which controls autonomic bodily functions like heart rate, breathing, consciousness, swallowing and many others. One cannot intervene in the brain stem surgically in any capacity, let alone resect a tumour, without risking any or all of these functions. 

In short, the challenges in treating this tumour are many, but one of them is the blood brain barrier, or BBB, the border of cells that prevents certain solvents circulating in the bloodstream from entering the brain. We have chemotherapy drugs that may treat the tumour, but because these drugs don’t cross the BBB, we just can’t get them there.

And here we are, for the very first time in history, using imaging and sound waves to open the blood brain barrier and deliver medication to the brain stem. How did you come to pull it off?

Lipsman: It was a combination of the right expertise at the right time. Dr. Rutka led the pre-clinical work that showed for the first time, using animal models, that it was safe and feasible to use focused ultrasound to deliver chemotherapy for DIPG. Essentially, the technology uses soundwaves to non-invasively make a temporary opening in the BBB, which lets the medication in. His work gave us compelling pre-clinical rationale to translate this to a human population.

At the same time, the work I led at Sunnybrook amassed an experience of BBB-opening in adult patients across multiple indications, including primary and secondary brain tumours, Alzheimer’s and Parkinson’s disease. This gave us compelling data that opening the BBB in human patients can be done safely. 

A five-year old patient is in the MRI during treatment

Walk me through January 4, the day you treated your first patient.

Lipsman: The patient is a five-year-old girl: the youngest allowed for our trial. We all had sensitivities, obviously, to treating such a young patient. There was certainly an emotional element. The patient’s family was hopeful but realistic, and really invested their trust in the research team. 

How many people were in the room?

Rutka: Around 20 people, including nurses, physicists, imaging scientists, anaesthetists, and Dr. Lipsman and myself. The family arrived around seven in the morning at the front doors of Sunnybrook. It was a long time coming—we had initially planned to do the procedure in December, but the patient unfortunately came down with a viral infection, so we had to wait. There was all this anticipation leading up to it, because the family really wanted to start the therapy as soon as possible. 

What happened first?

Lipsman: She was anaesthetized, and then we applied a head-immobilization device, which is essentially a crown or ring that keeps the head steady. That frame was then attached to a helmet-like device that delivers the ultrasound. The patient went into the MRI machine, which is where the entire procedure took place. First, we took about an hour and a half to do detailed imaging of the brain to make sure the tumour hadn’t changed since we last checked. Then we infused the chemotherapy, which we believe has to be actively circulating in the bloodstream when the BBB opens. 

How did you feel approaching this critical juncture in the procedure?

Rutka: We were a little anxious about what would happen, since it had never been done in this region of the brain before. A complication could be devastating in this region of the brain, since it could affect vital bodily functions, and may have led to a termination of the study. As we opened the BBB in a series of layers, we did special MRI sequences to look for things like bleeding and swelling in the brain. The treatment was extremely well tolerated, and there were no adverse events. 

Brain scan showing world-first MRI-guided focused ultrasound opening of blood-brain barrier for delivery of chemotherapy to a common brain tumour in children

That must have been an incredible relief. 

Lipsman: We didn’t see any abnormalities at all, which was the best-case scenario. In fact, the treatment went so well that we wondered if we had successfully opened the BBB in the first place, which we needed to confirm with another MRI with contrast. That’s because contrast will only go to the parts of the brain where the BBB is open.

We confirmed that it was actually open, which means the chemotherapy did get into the brain. That image was very exciting: the culmination of many years of research! After that was done, the patient came out of the scanner and was observed for two hours at Sunnybrook before moving back to SickKids. She was back in the recovery room making jokes two hours after the procedure. 

The next morning, she had another scan—this time, we confirmed that the barrier had closed. The closure is just as important as the opening, since we want to make sure it’s a reversible procedure. 

What happens next for this patient, and for the others in this study?

Lipsman: Every patient will undergo three treatments about four to six weeks apart. If all goes well, we’re looking to treat 10 patients in six to 12 months. 

What has the reaction from the medical community been like?

Rutka: Since we’ve launched the trial, I’ve had no shortage of people from around the world asking what the entry criteria are, since there are so many children worldwide afflicted with this condition. I hope this will be the start of several trials. For this trial, we chose the chemotherapy drug doxorubicin, a potent drug that’s never been used for brain tumours because it doesn’t cross the BBB. But there are a host of other drugs, either singly or in combination, that we can use to treat this disease. In the future, we can hopefully focus on the tumour’s molecular genetics to target the most effective drugs. 

What’s the potential impact of this research beyond DIPG?

Lipsman: This method—getting medication into the brain stem (or another part of the brain) via focused ultrasound—can be used for more than just chemotherapy. In theory, we could open the blood-brain barrier to deliver any promising medication to the brain. Parkinson’s is one we’re actively working on: we recently published a phase-one trial where we showed that in patients with genetic-form Parkinson’s, we can safely deliver promising enzyme replacement therapy. We’re also interested in metastasis: using BBB opening to deliver immunotherapy and antibody treatments for breast cancer that’s metastasized to the brain. 

In short, it’s a broad tool that could be used across many different indications. It’s all part of a larger trend in neurosurgery towards non- or minimally invasive methods of intervening in the brain.



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Britons with severe asthma could benefit from a 'life-changing' jab that can reduce the risk of attacks by up to 70 per cent.

The at-home injector pen contains a drug called tezepelumab – which blocks a key chemical that triggers attacks – and is more effective than current treatments.

Insiders have told The Mail on Sunday that the treatment is due to be approved by the National Institute for Health and Care Excellence (NICE) later this year following 'dramatic' trial results.

The move follows recent approval by the European Medicines Agency for its use across Europe.

BREATHE EASY: Tezepelumab pens, which can reduce the risk of severe asthma attacks by up to 70 per cent, could be in use by August

BREATHE EASY: Tezepelumab pens, which can reduce the risk of severe asthma attacks by up to 70 per cent, could be in use by August

Doctors have spoken of 'remarkable' transformations following a course of the drug, which also causes far fewer side effects compared with potent steroid inhalers.

One young sufferer completed a mountain biking marathon after the jab having previously been unable to exercise at all.

Another patient, who had recently been hospitalised several times with asthma attacks, said the drug had 'given me my life back'.

Roughly eight million Britons suffer with asthma. It develops when the breathing tubes that carry air in and out of the lungs become inflamed and narrow. For most, mild breathing trouble happens only occasionally and is usually triggered by allergies or exercise.

The majority control their symptoms with inhalers. Sufferers are prescribed two types: one, containing steroids, to prevent attacks and another to relieve symptoms when an attack occurs. But around 200,000 asthmatics have a severe form of the disease.

They are usually reliant on stronger medicines including steroids, which come with a plethora of side effects including weight gain, nose bleeds and chest infections, often requiring hospital admissions.

Dr Ian Pavord, Professor of Respiratory Medicine at the University of Oxford, who has led trials of the new drug, says: 'I used to see my job as managing an orderly decline. Our only option was steroid tablets which was pretty depressing.

'After a few months, patients would start to get side effects which were often worse than the disease. But we had no choice, we had to keep people alive.'

But over the last decade, a new class of drug, called monoclonal antibodies, has offered hope to these patients.

Monoclonal antibodies are delivered as an injection or infusion, and block specific proteins released by the immune system that worsen lung inflammation.

As they are a more targeted solution, they involve fewer side effects and complications – but the current generation of monoclonal antibodies tend not to work so well in patients who have had asthma since childhood because, in some, inflammation is triggered by an over-reaction of the immune system, which is more complicated to stop.

However, tezepelumab is highly effective in all patients, studies have shown.

Roughly eight million Britons suffer with asthma. It develops when the breathing tubes that carry air in and out of the lungs become inflamed and narrow (stock photo)

Roughly eight million Britons suffer with asthma. It develops when the breathing tubes that carry air in and out of the lungs become inflamed and narrow (stock photo)

It works by blocking a chemical, released by the lining of the airway, which triggers a cascade of proteins that drive inflammation. 'It's a bit like switching the lights off at the mains, or turning off the water supply,' says Prof Pavord.

'Turning off this chemical has a much broader effect on dampening the inflammatory response.'

'You get more bang for your buck with this drug,' he adds.

'We can help a wider variety of patients and it has a more dramatic effect than other, similar drugs.

'We think we can achieve remission from the disease in at least one in three patients with this drug – possibly many more.'

In 2021, a major trial involving 1,000 international patients found that injecting the drug once a month for a year slashed asthma attacks by 71 per cent.

Professor Pavord recalls that several patients on his clinical trial were 'unrecognisable' after taking tezepelumab for a year.

'One was a 28-year-old woman who struggled to breathe at night and had gained five stone over the previous few years because of the steroids,' he says.

'Suddenly, she'd dropped the extra weight and was able to breathe fine – even at night.

'She was able to run around after her three young children without getting breathless, and that was the most important thing to her.

'Another patient had been confined to a wheelchair and relied on an oxygen cylinder pretty much daily to breathe.

'After the trial, he no longer needed it. We expect the NICE approval to come in August.

'It will be exciting to see the effect on patients in clinic.'

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Introduction

Approximately one in five people with COPD are also living with frailty.1 Frailty is a multidimensional syndrome, characterised by decreased reserve and diminished resistance to stressors.2 It is relevant across diagnoses, including multimorbidity, and can provide a holistic measure of a person’s health and risk of adverse outcomes. People with both COPD and frailty experience poorer physical and mental health,3 higher risk of readmission4 and mortality,5 and are at higher risk of not receiving disease modifying treatments3,6 compared to those with COPD without frailty. Identifying frailty in respiratory research and practice has been recognised as important by public and professional stakeholders.7

Several measures have been used to identify frailty in people with COPD, and there is no universal agreement on which frailty measure should be used.8 While comprehensive geriatric assessment is the gold-standard approach to identify this syndrome and direct appropriate clinical care,9 brief tools to approximate frailty are essential to identify potential candidates for additional support, and measure frailty as a clinical or research outcome. The Fried Frailty Phenotype (FFP) is one of the most well-established measures of frailty,8 comprising five characteristics: unintentional weight loss, exhaustion, low physical activity, slowness and weakness.10 The Short Physical Performance Battery (SPPB)11 incorporates static balance tests, four-metre gait speed (4MGS), and the five sit-to-stand test, and has recently been recommended by the European Medicines Agency for baseline characterisation of physical frailty in people aged ≥65 years enrolled in clinical trials. Both measures are responsive to change following pulmonary rehabilitation3,12 and predictive of adverse events,13,14 including mortality.14 Using the FFP, people with COPD and frailty have been found to have higher risk of mortality compared to people with COPD without frailty (adjusted HR 1.4; 95% CI 0.97 to 2.0);15 and compared to people with neither COPD nor frailty (adjusted HR 2.7, 95% CI 1.07–6.94).16 While SPPB scores are predictive of mortality in COPD,14 this has not been explored with SPPB scores dichotomised by thresholds for frail versus not frail.

Although both the FFP and SPPB measures have been used to identify people living with frailty, little is known about the comparative characteristics of these measures when used with people with COPD. One study with 395 lung transplant candidates measured frailty using both measures to assess their construct and predictive validity.6 Despite more people being categorised as frail using FFP versus SPPB (28% vs 10%), both measures were associated with physiological and functional baseline characteristics and outcomes. However, only 30% of participants had COPD, and this study did not explore associations between the frailty measures and broader domains of health (eg, psychological, quality of life). Moreover, the multivariate modelling did not control for any widely used and validated prognostic index (eg, Age Dyspnoea Obstruction [ADO] or Body mass index, Obstruction, Dyspnoea, Exercise performance [BODE]).17

How the FFP and SPPB identify people living with frailty, and their varying predictive properties, may have important implications for their use and interpretation. Yet, these measures have not been directly compared in people living with COPD. Differences in the frailty definitions selected may modify the target population and interventional response and/or inform how evidence relating to frailty is synthesised. To support data-driven decision-making in clinical practice and research, this study aimed to compare the FFP and SPPB measures of frailty in people with stable COPD. Objectives were to (a) describe prevalence of, and overlap in, identification of frailty using the two measures; (b) compare disease and health characteristics in those identified as living with frailty using the two measures, and (c) compare the predictive value of the two frailty measures in relation to survival time.

Methods

Design

Cohort study.

Setting

Hillingdon Borough, North West London, United Kingdom.

Participants

Participants were consecutively identified and recruited from community respiratory and pulmonary rehabilitation assessment clinics, between November 2011 and January 2015. Eligible participants included people aged 35 years or over with a physician diagnosis of COPD (consistent with GOLD criteria18), and appropriate for pulmonary rehabilitation referral in line with British Thoracic Society Guidance: able to walk at least five metres, experiencing functional impairment due to breathlessness, and no previous supervised pulmonary rehabilitation in the previous 12 months. Exclusions included exacerbation of their COPD within the past four weeks that required a change in medication, or if moderate-intensity exercise was deemed unsafe (eg, due to unstable cardiac condition). Data from this ongoing research cohort have been published previously.3,19 The current study includes those with complete data for both frailty measures. Where people were assessed for pulmonary rehabilitation more than once during the study period, only their first assessment was included.

Frailty Measures

We compared the FFP and the SPPB, collected at baseline assessments.

The five characteristics of the FFP were assessed, respectively, using self-report unintentional weight loss history, two self-report questions on exhaustion from the Centre for Epidemiological Studies Depression (CES-D) questionnaire, self-reported physical activity from the modified Minnesota Leisure-Time physical activity questionnaire, handgrip dynamometry (weakness), and 4MGS (slowness). The 4MGS was completed using processes validated in COPD20 on a flat, unobstructed course, following a demonstration by the assessor. Participants were able to use their usual walking aids if applicable, and the faster of two attempts completed sequentially without rest was used. Presence or absence of each FFP characteristic was assessed and scored based on standardised criteria, described in detail previously.3 People meeting three or more criteria were considered to be living with frailty;10 those meeting 1–2 (prefrail) or 0 criteria (robust) were considered not to be living with frailty.

For the SPPB,11,21 performance in static balance, 4MGS, and five sit-to-stand tests were each assessed following a standardised protocol from the National Institute of Ageing, and scored from 0 to 4. The sit-to-stand component followed processes validated in COPD,22 including the use of a straight-backed armless chair with a floor-to-seat height of 48cm. Participants began with an initial stand and sit: those completing this successfully completed the five sit-to-stands, while the test was terminated for those unable to complete this initial manoeuvre. Each SPPB component contributes to a total score from 0 to 12, with higher scores indicating robustness. People scoring ≤7 were considered to be living with frailty,21 in line with European Medicines Agency guidance. As there is no consensus over optimal cut-offs when using the SPPB, we also conducted sensitivity analyses using alternative cut-off values of ≤823 and ≤9.24

Analysis

Prevalence and Overlap in Identification of Frailty

The prevalence of participants identified as living with frailty using each measure were described as percentages, and agreement described using Cohen’s Kappa. Agreement was categorised: slight ≤0.20, fair 0.21–0.40, moderate 0.41–0.60, substantial 0.61–0.80, almost perfect 0.81–1.00.25 Overlap in frailty categorisation between the two measures was illustrated using a Venn diagram. Post-hoc analysis explored areas of convergence and divergence between the measures through tabulating and examining inter-item correlations.

Comparison of Population Characteristics

The following characteristics (scale, ranges if applicable) from participants’ baseline assessment were described for those identified as living with or without frailty by each measure: age (years); forced expiratory volume in one second percent-predicted (FEV1% predicted); breathlessness (Medical Research Council [MRC] Dyspnoea, 1–5); Age Dyspnoea Obstruction (ADO) Index (0–14); Body Mass Index (BMI); comorbidities (age-adjusted Charlson comorbidity index); exercise capacity (Incremental Shuttle Walk Test [ISWT] distance in metres); anxiety symptoms (Hospital Anxiety and Depression Scale [HADS], 0–21); depression symptoms (HADS, 0–21); health-related quality of life (Chronic Respiratory Questionnaire Dyspnoea [5–35], Emotion [7–49], Fatigue [4–28] and Mastery [4–28] domains); and independence in basic activities of daily living (Katz questionnaire, scores 1–6 dichotomised some dependence [scores 1–5] and independent [score 6]). Questionnaires and physical measures were collected during their assessment in an outpatient consultation room. Additional information about these measures can be found within the Supplementary Material Table S1.

Following distribution checks for normality, characteristics were described using mean/medians and standard deviations/interquartile ranges (as appropriate) for continuous variables, and using frequencies and percentages for categorical variables. Independent t-tests/Mann Whitney U-tests and chi squared tests (as appropriate) were used to compare those identified as living with and not living with frailty within each measure. A p-value of less than 0.01 was used as the threshold for statistical significance to reduce risk of type 1 error due to multiple testing.26

Predictive Value for Mortality

It is recommended that, in survival analysis, there should be a minimum of 10 events per independent variable included in the model.27 As there were 376 deaths, there were sufficient cases for multivariable modelling.

Participants were followed up prospectively, and date of death was identified from hospital records and/or central National Health Service databases. Time to death in days was calculated from the date of assessment until date of death. Participants who survived were censored on 29th January 2021.

Kaplan–Meier plots and log rank tests were used to assess whether each frailty measure identified groups with different survival curves. The following disease and health characteristics were also assessed for associations with mortality using univariate Cox regression (or appropriate alternatives if proportional hazard assumption was violated), to inform subsequent adjusted analysis: Body Mass Index, comorbidity index, exercise capacity, anxiety, depression, independence in activities of daily living, and pulmonary rehabilitation completion. In separate models for each frailty measure, variables associated with mortality in univariable analyses (p < 0.05) were included in multivariable Cox Regression analysis (or appropriate alternatives if proportional hazard assumption was violated). In all cases, the multivariable analyses included checking for collinearity (r < 0.75), and controlling for sex and the ADO index: the former to account for known sex differences in mortality,28 the latter to determine the prognostic value of the FFP and SPPB over and above an established validated prognostic indicator.29 Analyses were undertaken using IBM SPSS Statistics 27.30

Ethical Approval

Study procedures complied with the Declaration of Helsinki. All participants gave informed consent. The recruitment and follow-up of the cohort received ethical approval from the West London (11/H0707/2) and London Camberwell St Giles (11/LO/1780) research ethics committees.

Results

Participant Characteristics

Of 1084 unique referrals for people with COPD during the study period, 1019 attended their assessment. Of these, 716 (70%) were eligible to be included in the research cohort. Of 716 individual participant assessments during the study period, SPPB scores were missing for 2 participants and the remaining 714 had data for both frailty measures. Four-hundred and twenty-one (59%) were male, and the mean (SD) age was 69.9 (9.7) years. Participant characteristics are shown in Table 1.

Table 1 Participant Characteristics (n = 714)

Prevalence and Overlap in Frailty Identification

Similar proportions of the sample were identified as living with frailty using the FFP (26.2%, n = 187) and SPPB (23.7%, n = 169) measure. There was moderate agreement between the measures (K = 0.469, SE = 0.038, p = <0.001), with matching classifications of frail or not frail in 572 (80.1%) of cases (Figure 1). Sensitivity analysis using SPPB cut-offs of ≤8 and ≤9 led to higher proportions of the sample being identified as frail (33.6% [n = 240] and 46.1% [n = 329], respectively), but lower proportions of matching classifications (76.9% [n = 549] and 70.0% [n = 500], respectively) and lower kappa agreement scores with the FFP (0.452 and 0.377, respectively).

Figure 1 Venn diagram of frailty classification using Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB) measures (n = 714).

Post-hoc analyses of inter-item correlations (Table 2) suggest that classification discrepancies may have arisen particularly from the weight loss and exhaustion components of the FFP, both of which show the lowest correlations with each SPPB item. Balance was the SPPB item least correlated with the FFP items.

Table 2 Inter-Item Correlation Between Fried Frailty Phenotype and Short Physical Performance Battery Components

Disease and Health Characteristics by Frailty Measure

Participants identified as living with frailty using either the FFP or SPPB were significantly older and had more comorbid conditions but did not show substantial differences in FEV1% predicted or BMI (Table 3). Participants with frailty identified using either measure scored lower on functional exercise capacity and reported more breathlessness and dependence in activities of daily living, higher depression symptoms, and poorer quality of life on the CRQ domains of fatigue, emotion, and mastery. Only participants identified as living with frailty using the FFP (not SPPB) reported significantly poorer anxiety and worse CRQ dyspnoea. Sensitivity analysis using cut-offs of ≤8 and ≤9 for SPPB found similar patterns, but as the cut-off score increased the SPPB showed significant differences in anxiety (≤8 only) and CRQ dyspnoea (≤8 and ≤9) between those with and without frailty.

Table 3 Comparison of People Identified as Living with Frailty versus without Frailty Using the Fried Frailty Phenotype and Short Physical Performance Battery (n = 714)

Predictive Value in Relation to Survival

Of the 714 participants, 376 (52.7%) had died by 29th January 2021. Mean survival time was 2270 days (95% CI 2185–2355); approximately 6 years. For both the FFP and SPPB measure, a higher proportion of people with frailty had died by end of the study period than the non-frail groups: FFP 71.7% (n = 134) with frailty vs 45.9% (n = 242) without frailty died; SPPB 72.2% (n = 122) with frailty vs 46.6% (n = 254) without frailty died.

Survival time was approximately 2 years shorter for those with frailty versus without frailty, using either the FFP (mean 1795 days [95% CI 1629–1961] vs mean 2439 days [95% CI 2344–2533]) or SPPB (mean 1698 days [95% CI 1530–1866] vs 2435 days [95% CI 2342–2527]). As illustrated in the Kaplan–Meier plots in Figure 2, both measures identified a frail group with significantly shorter survival than the group who were not frail.

Figure 2 Kaplan–Meier plots showing survival of frail vs non-frail groups using the Fried Frailty Phenotype and Short Physical Performance Battery.

Univariate Cox regression analysis found that BMI, comorbidities, and exercise capacity were also significantly related to survival, while activities of daily living, anxiety, depression, and pulmonary rehabilitation completion were not. The final multivariable models for each frailty measure and survival included ADO and sex (as forced variables) as well as comorbidities, exercise capacity and BMI. When controlling for these variables, frailty measured using the FFP measure remained a significant independent predictor of survival, while frailty measured using the SPPB did not. However, both showed comparable point estimates, suggesting in either case an increase in mortality risk for those with frailty (Table 4). Sensitivity analysis using the alternative SPPB cut-offs of ≤8 and ≤9 found similar results (≤8 cut-off HR = 1.73, 95% CI 1.41–2.12 and aHR = 1.00, 95% CI 0.77–1.29; ≤9 cut-off HR = 1.78, 95% CI 1.45–2.18 and aHR = 1.04, 95% CI 0.81–1.33).

Table 4 Univariable and Multivariable Prediction of Mortality Comparing the Fried Frailty Phenotype and Short Physical Performance Battery

Discussion

This study compared the properties of the FFP and SPPB measures in people with COPD. We found moderate agreement in frailty classification, including matching classification of frail or not frail in 80% cases. Participants identified as living with frailty using either measure differed significantly from non-frail participants in similar ways: they were older, had more comorbidities and lower functional exercise capacity, and reported more dependence in activities of daily living, higher depression symptoms, and poorer health-related quality of life. People identified as frail using the FFP also reported significantly worse anxiety symptoms. Both measures showed predictive value in relation to survival. While the FFP provided slightly higher independent predictive value than the SPPB when used alongside other measures, including the ADO Index, this difference was marginal and trivial.

This study is the largest to date to use either the validated version of the FFP measure or the SPPB to predict mortality in people with COPD. Building on prior work by Singer et al that compared these measures in 395 candidates for lung transplant,6 we also found approximately 80% matching classifications between the two measures. Moreover, our adjusted hazard ratios for mortality were similar to those for delisting or death before lung transplant (FFP aHR 1.30, 95% CI 1.01–1.67; SPPB aHR 1.53, 95% CI 1.19–1.59).6 Together with smaller studies of the FFP13,16 and SPPB14 measures in people with COPD, there is growing evidence that each measure provides additional prognostic information when predicting mortality in this population, even when including established indexes such as ADO, in the current study, and BODE in the study by Fermont et al14

The FFP and SPPB both identified a group with multidimensional health challenges. Corroborating previous work, we found that around 1 in 4 people with COPD attending pulmonary rehabilitation were living with frailty31,32 and that those with frailty on either measure had lower exercise capacity,6,12 poorer physical function33,34 and increased breathlessness,12,13,33,34 but little difference in lung function.6,12,33 We extend these findings by illustrating associations of frailty, on either measure, with other dimensions of health, including higher depression symptoms, increased dependence in activities of daily living, and lower health-related quality of life. These differences tended to not only be significant but clinically meaningful.35,36 These wider correlates of frailty are in line with qualitative descriptions of the multidimensional losses experienced by people living with both COPD and frailty.37 The FFP measure additionally discriminated between people with different levels of anxiety and CRQ dyspnoea where the SPPB did not. This may reflect closer links between these broader self-reported aspects of health and the self-reported components of the FFP, such as exhaustion.

Measurement of frailty in respiratory research and care is increasingly recognised as important.7,38 Given varying resources and equipment available across settings (eg, handgrip dynamometers), it is helpful to know that there is substantial overlap between those identified as frail using the FFP or SPPB measure and that both measures identify people experiencing multidimensional health challenges. Decisions driven by pragmatic considerations can now be made with an understanding of the different emphases of each measure. For example, the FFP may identify people with more psychological symptoms and be less discriminant in relation to the presence of balance difficulties, while the SPPB may be less discriminant in relation to presence of exhaustion and weight loss. Moreover, this knowledge may inform more purposive use of either measure, for example, depending on the theorised mechanisms and targets of a particular intervention. Importantly, it should be acknowledged that both the FFP and SPPB are only surrogate markers of frailty: a comprehensive geriatric assessment remains the gold-standard approach to identify this syndrome and direct appropriate clinical care.9

Our data show that those identified as frail using the FFP or SPPB are twice as likely to die in the subsequent six years or so than their non-frail counterparts. Although there are limited trial data, growing evidence supports the potential of pulmonary rehabilitation in reversing frailty,3,32 but also of the difficulties those with frailty face in completing this intervention.3,37 Adapted pulmonary rehabilitation approaches for this group that integrate comprehensive geriatric assessment may have a role here,39 and work in this area is ongoing.40 Alongside this, the increased risk of mortality and poorer multidimensional health in those with COPD and frailty should also prompt thinking around the information and support needs of this group, which might include a role for integrated working with palliative care specialists and advance care planning.41

Although the single centre design and restriction to people attending an initial pulmonary rehabilitation assessment may reduce external validity, the large sample size and consecutive recruitment may support some generalisability to other outpatient cohorts. The focus on baseline data (with only survival as follow-up data) also meant little frailty data was missing for this cohort. This analysis included relevant disease characteristics, physical tests and self-reported health across multiple dimensions, including physical and psychological symptoms, activities of daily living and quality of life. This allowed us to comprehensively characterise those with frailty, but also adjust for several important confounders. These measures are routinely collected by skilled professionals during clinical assessments, supporting internal validity. It is important to acknowledge that including the separate component variables for Age, Dyspnoea and Obstruction may have accounted for more variance in the multivariate modelling than the composite ADO index, however it was deemed valuable to understand the prognostic value of the FFP and SPPB over and above an established prognostic indicator. Our long-term mortality follow-up helps demonstrate the value of two common frailty measures over an extended duration, but future work exploring comparative predictive value in relation to hospitalisation and readmission may also be useful. Importantly, this comparison only included two measures of frailty, both of which require physical tests which are not always feasible or practical. Further comparative work exploring the properties of other types of frailty measure including self-report screening tools (eg, FRAIL Scale42) and clinical-judgement-based approaches (eg, the Clinical Frailty Scale43) in COPD is needed. In addition, applicability across different ethnicities is unknown due to lack of data on this characteristic.

In conclusion, we found that in stable COPD, both the FFP and SPPB measures identify people with multidimensional health challenges and increased mortality risk. When used alongside other established measures, including the ADO index, both the FFP and SPPB frailty measures offer added value in predicting mortality.

Data Sharing Statement

All data requests should be submitted to Dr William D-C Man ([email protected]) for consideration. Access to anonymised data might be granted following investigator review.

Acknowledgments

Thank you to the participants for contributing their time to this research, and to Jane Canavan, Sarah Jones, and the clinical teams for supporting data collection. Matthew Maddocks and William DC Man are co-senior authors for this study.

Funding

This study was funded by a Medical Research Council New Investigator Research Grant and a National Institute for Health and Care Research (NIHR) Clinician Scientist Award (DHCS/07/07/009) held by WDCM and a NIHR Career Development Fellowship (CDF-2017-10-009) held by MM. RB is funded an NIHR Clinical Doctoral Research Fellowship (ICA-CDRF-2017-03-018). CE is funded by a Health Education England/National Institute of Health Research Senior Clinical Lectureship (ICA-SCL-2015-01-001). This research was supported by the NIHR Collaboration for Leadership in Applied Health Research and Care South London, now recommissioned as NIHR Applied Research Collaboration South London. This publication presents independent research funded by the NIHR. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, NIHR or the Department of Health and Social Care.

Disclosure

LJB, REB, SP, JAW, OP, SSCK, WG, CJE, and MM have no conflicts to declare. CMN reports personal fees from Novartis, outside the submitted work. WDCM reports grants from Medical Research Council, National Institute for Health and Care Research, and British Lung Foundation, during the conduct of the study. WDCM also involved in educational activities with Mundipharma, Novartis, and European Conference and Incentive Services DMC; and is also part of the advisory board for Jazz Pharmaceuticals, outside the submitted work. The authors report no other conflicts of interest in this work.

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41. Brighton LJ, Miller S, Farquhar M, et al. Holistic services for people with advanced disease and chronic breathlessness: a systematic review and meta-analysis. Thorax. 2019;74(3):270–281. doi:10.1136/thoraxjnl-2018-211589

42. Morley JE, Malmstrom TK, Miller DK. A simple frailty questionnaire (FRAIL) predicts outcomes in middle aged African Americans. J Nutr Health Aging. 2012;16(7):601–608. doi:10.1007/s12603-012-0084-2

43. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. Can Med Assoc J. 2005;173(5):489–495. doi:10.1503/cmaj.050051

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Asthma is a chronic inflammatory disease of the lungs. The airways in the lungs become narrow due to inflammation and tightening of the muscles around the small airways and also due to excess mucus. It is characterised by airflow obstruction and triggers bronchospasms.

Signs and symptoms of asthma includes shortness of breath, chest tightness, recurrent episodes of wheezing and cough. These symptoms vary from person to person. The symptoms get worse during night or with exercise.

Asthma is caused by a combination of environmental and genetic interactions. Allergies can raise the development of asthma, certain respiratory infections such as RSV can affect children. Exposure to tobacco smoke and other sources of air pollution can increase the risk

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There is currently no precise test for the diagnosis, which is typically based on the pattern of symptoms and response to therapy over time. The condition is suspected with a history of recurrent wheezing, coughing or difficulty breathing. The main tests include spirometry, peak flow test and FeNO test.

Asthma treatment aims in reducing the inflammation and bronchoconstriction of the airways. This involves the anti-inflammatory agents for the mildest symptoms. Other medications involve, bronchodilators, anticholinergics, corticosteroids and biologics. Avoidance of triggers is a key component of improving control and preventing attacks.

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Report Highlights

Global Insight Service's, Asthma - Drug Pipeline Landscape, 2022 report provides an overview of the Asthma pipeline drugs. This report covers detailed insights on Asthma drugs under development, assessment by target, mechanism of action, route of administration and molecule type. Product pipeline by companies, stage of development and key regulatory designations, deals and milestones have been presented to provide insights and thus help industry participants in their decision making. Asthma pipeline report helps gain insights on drugs which are under development stage of drug development process across globally.

Scope

The pipeline landscape report provides analysis of pipeline products based on several stages of development ranging from Discovery to Pre-Registration. The report provides a review of pipeline therapeutics by companies based on information derived from company and industry-specific sources. The pipeline report covers assessment of therapeutics by mechanism of action (MoA), drug target, route of administration (RoA) and molecule type. Comprehensive profiles of the pipeline products with details such as company overview, development stage; molecule type, target, mechanism of action, route of administration, dosage form, regulatory designations, key deals, clinical trials, and key upcoming milestones are included.

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Reasons to Buy

Helps to find and recognize significant therapeutics under development. Thorough understanding of pipeline structure and helps in developing corrective measures for pipeline projects.
Effective R&D strategies can be developed with deep knowledge of competitor information, analysis, and insights.

Plan collaborations with various industry partners that have role in some or the other stage of drug development such as contract manufacturing, co-development, contract research organization and commercialization etc.

Helps to create in-licensing and out-licensing opportunities by identifying prospective partners with attractive projects to expand business potential and scope.

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Methodology

The research process includes extensive secondary research on public domain and other authentic sources to add or update the pipeline products information. The secondary research sources include, but are not limited to company websites, annual reports, financial reports, company pipeline chart, investor presentations and SEC filings, journals and conferences, and clinical trials registries.

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Robert V. O’Toole, MD

A randomized clinical trial of more than 12,000 patients treated at medical centers in the US and Canada suggests aspirin was as effective as low-molecular-weight heparin for preventing life-threatening blood clots in patients hospitalized with fractures.

A noninferiority trial of adults who had a fracture of an extremity treated operatively or who had any pelvic or acetabular fracture, results of the study indicate use of aspirin was noninferior for preventing death and was associated with low incidences of deep-vein thrombosis and pulmonary embolism.

“Many patients with fractures will likely strongly prefer to take a daily aspirin over receiving injections after we found that both give them similar outcomes for prevention of the most serious outcomes from blood clots,” said lead investigator Robert V. O’Toole, MD, chief of Orthopaedics at the R Adams Cowley Shock Trauma Center at the University of Maryland Medical Center (UMMC), in a statement from UMMC. “We expect our findings from this large-scale trial to have an important impact on clinical practice that may even alter the standard of care.”

Led by Toole, along with collaborators from UMMC and the Major Extremity Trauma Research Consortium, the Prevention of Clot in Orthopaedic Trauma (PREVENT CLOT) trial was designed pragmatic, multicenter, randomized, noninferiority trial that enrolled the aforementioned patient population and randomized them to low-molecular-weight heparin (enoxaparin) 30 mg twice daily or aspirin 81 mg twice daily during hospitalization. In total, the trial enrolled 12,211 patients from 21 trauma centers in the US and Canada between April 2017 and August 2021, with 6101 patients randomized to aspirin and 6110 randomized to low-molecular-weight heparin.

The study cohort had a mean age of 44.6±17.8 years, 0.7% had a history of venous thromboembolism, and 2.5% had a history of cancer. When examining thromboprophylaxis trends, investigators found the mean duration of in-hospital thromboprophylaxis was 8.8±10.6 days and the median duration of thromboprophylaxis prescribed at discharge was a 21-day supply. Per trial protocol, post-discharge thromboprophylaxis was conducted according to the protocols of each trauma center. The primary outcome of interest for the trial was all-cause mortality at 90 days. Secondary outcomes of interest included the incidence of nonfatal pulmonary embolism, deep vein thrombosis, and bleeding complications.

Upon analysis, a total of 47 (0.78%) deaths occurred among the aspirin group and 45 patients in the low-molecular-weight heparin group (difference, 0.05 percentage points [96.2% CI, -0.27 to 0.38]; P <.001 for a noninferiority margin 0.75 percentage points. Analysis of secondary outcomes indicated pulmonary embolism occurred in 90 patients (90-day probability, 1.49%) among the aspirin group and in 90 patients (90-day probability, 1.49%) among the low-molecular-weight heparin group (difference, 0.00 percentage points [95% CI, -0.43 to 0.43]). Further analysis indicated deep vein thrombosis occurred in 2.51% of patients among the aspirin group and 1.71% among the low-molecular-weight heparin group (difference, 0.80 percentage points [95% CI, 0.28 to 1.31]). Evaluation of bleeding complications and serious adverse indicated event rates were similar between the study arms.

“This relatively small difference was driven by clots lower in the leg, which are thought to be of less clinical significance and often do not require treatment,” said study investigator Deborah Stein, MD, MPH, professor of Surgery at UMSOM and director of Adult Critical Care Services at UMMC.

This study, “Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture,” was published in the New England Journal of Medicine.

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By: Charles Lascano, MD, CAQSM, DABFM.

Sports Medicine Physician. Sanitas Medical Centers.

 

Para leer en Español

Mindfulness is a type of meditation in which one focuses on being intensely aware of what is sensing and feeling in the moment, without interpretation or judgment. Practicing mindfulness involves breathing methods, guided imagery, and other practices to relax the body and mind, and help reduce stress. Mindfulness meditation has been studied in many clinical trials. The overall evidence supports the effectiveness of this meditation for various conditions, including anxiety, stress, depression, pain, sleep problems, and high blood pressure.

Below are mindfulness exercises which you can practice regularly anywhere and anytime but it is recommended to set aside time when you can be in a quiet place without distractions or interruptions.

Exercise #1. Mindful breathing. Sit comfortably with your back straight, feet flat on the floor and hands over your lap. Breathing through your nose, focus on your breath moving in and out of your body. If physical sensations or thoughts interrupt your meditation, note the experience, and then return your focus to your breath.

Exercise #2. Body scan meditation. Same position of mindful breathing or lie on your back with your legs extended and arms at your sides, palms facing up. Focus your attention slowly and deliberately on each part of your body, in order, from toes to head or head to toes. Be aware of any sensations, emotions or thoughts associated with each part of your body.

Exercise #3. Walking meditation. Find a quiet place 10 to 20 feet in length and begin to walk slowly. Focus on the experience of walking, being aware of the sensations of standing and the subtle movements that keep your balance. When you reach the end of your path, turn, and continue walking, maintaining awareness of your sensations.

Exercise #4. Mindful eating. Next time you’re eating a meal or snack, slow down and focus all your senses on the experience of eating: what does your food look like, smell like, taste like, feel like as you chew it? Keep your attention on this as you take each bite.

Exercise # 5. Five Senses. This involves tuning your senses to the environment around you, taking a moment to note five things you can see, four things you can feel, three things you can hear, two things you can smell, and one thing you can taste.

 

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In patients with chronic obstructive pulmonary disease (COPD), long-acting muscarinic antagonists (LAMA)/long-acting beta-2 agonists (LABA) combinations are more effective than monotherapy or placebo for most exercise capacity and physical activity outcomes, according to study findings published in Respiratory Research.

Investigators conducted a systematic literature review and meta-analysis of randomized clinical trials to assess the effect of combination LAMA/LABA bronchodilators vs placebo or LAMA or LABA monotherapy on outcomes related to exercise capacity and physical activity in patients with COPD.

The literature search was performed in the MEDLINE, Central, and Embase databases for articles published between January 1, 2012, and December 31, 2021. Eligible trials included patients at least 40 years of age diagnosed with COPD who had a postbronchodilator forced expiratory volume at 1 second/forced vital capacity of less than 0.7.

A total of 17 randomized controlled, double-blind trials with 4041 patients were included. Of those patients, 2964 were treated with the LAMA/LABA combination, 1901 with placebo, 1070 with LAMA, and 755 with LABA.

The LAMA/LABA combination treatment was associated with significantly better physical endurance compared with placebo, based on the endurance shuttle walk test (ESWT) and constant work rate cycle ergometry (CWRCE). LAMA/LABA combinations had favorable results compared with monotherapy, although they were not statistically significant, according to use of ESWT (standardized mean differences [SMD], 0.16; 95% CI, -0.00 to 0.33) and CWRCE (SMD, 0.06; 95% CI, -0.00 to 0.13).

A meta-analysis of 4 studies that compared LAMA/LABA with monotherapies (n=634) found significant differences in the 6-minute walking test (6MWT) in favor of the LAMA/LABA therapy combination (SMD, 0.17; 95% CI, 0.02-0.33).

Our review showed that LAMA/LABA combination therapy was superior to placebo and monotherapy in terms of evaluating exercise capacity and physical activity in patients with COPD in almost every comparison.

LAMA/LABA combinations were significantly superior to placebo and monotherapy regarding steps per day. For daily duration activity, the LAMA/LABA combination significantly reduced the duration of at least 1.0 to 1.5 metabolic equivalent of task (MET) activities compared with monotherapy. For moderate physical activity, LAMA/LABA therapy increased the duration of 2.0 or more MET activities. Regarding vigorous physical activity (≥3.0 METs), LAMA/ LABA therapy was superior to monotherapy and placebo, although the latter findings were not statistically significant.

Daily activity-related energy expenditure was increased in the LAMA/LABA group compared with the placebo group (SMD, 0.28; 95% CI, 0.12-0.44). The placebo group had more inactive patients (<6000 steps/day) compared with the LAMA/LABA group (odds ratio, 0.27; 95% CI, 0.14-0.51; 1 study, n=267).

In sensitivity analysis stratified according to study design when heterogeneity was present, the LAMA/LABA combination’s favorable results vs monotherapy were confirmed in 6MWT and steps per day. For vigorous physical activity, LAMA/LABA therapy was superior to both monotherapies with a significant heterogeneity (I2 = 69%); owing to the inclusion of 2 studies, the sensitivity analysis was based on individual study results.

Limitations include differences among the studies on variables used to measure physical activity. In addition, in some analyses different LAMA/LABA combinations were compared with different LAMA or LABA monotherapies, and outcome evaluation times were different, ranging from 3 to 12 weeks. Also, statistical heterogeneity was high in some comparisons, which limited the validity and the generalizability of the findings.

“Our review showed that LAMA/LABA combination therapy was superior to placebo and monotherapy in terms of evaluating exercise capacity and physical activity in patients with COPD in almost every comparison,” stated the researchers. “Enhancing physical activity and exercise capacity in COPD patients might lead to improve their quality of life and minimize the burden of the disease.”

Disclosure: This study was funded by Boehringer Ingelheim Spain. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

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Moderna’s vaccine against respiratory syncytial virus (RSV) was 83 percent effective at preventing lower respiratory tract disease in adults aged 60 and older in a large clinical trial, the company announced on Tuesday.

Based on the results, Moderna said it intends to submit the vaccine for Food and Drug Administration (FDA) approval in the first half of 2023. The announcement puts Moderna into a crowded marketplace of RSV vaccines for older adults, including giants GlaxoSmithKline and Pfizer.

Both companies have applied for FDA approval of their respective RSV vaccines and expect decisions in May.

Moderna said the vaccine was 83.7 percent effective at preventing two key symptoms, like fever, cough or difficulty breathing. The vaccine was 82.4 percent effective at preventing severe RSV cases with three or more symptoms present, the company said.

There is no vaccine for RSV in either adults or children. In healthy adults and older children, RSV typically causes mild, cold-like symptoms that go away with moderate rest and self-care. But it can result in severe illness in infants and older adults.

RSV infections kill between 6,000 and 10,000 adults over age 65 every year and results in 60,000 to 120,000 hospitalizations, according to the Centers for Disease Control and Prevention. RSV kills between 100 and 300 children in the U.S. each year.

Like the flu, RSV season usually occurs during colder weather, though this year it hit unusually hard and early, contributing to a wave of respiratory infections that led to overwhelmed hospitals nationwide.

Moderna’s RSV vaccine uses the same messenger RNA technology as the company’s COVID-19 shots. The company said its vaccine is also being tested in an ongoing early stage trial in pediatric populations.

“Today’s results represent an important step forward in preventing lower respiratory disease due to RSV in adults 60 years of age and older. These data are encouraging, and represent the second demonstration of positive phase 3 trial results from our mRNA infectious disease vaccine platform after, Spikevax, our COVID-19 vaccine,” Moderna’s CEO Stéphane Bancel said in a statement.

The company said it will publish the full data set in a peer reviewed journal and present it at an upcoming infectious disease conference.

Moderna said its Phase 3 trial enrolled about 37,000 people ages 60 and older in 22 countries including the U.S. About half were given a single dose of the RSV vaccine and the other half received a placebo.

The vaccine was well tolerated with no safety concerns. Most adverse reactions were mild or moderate and the most commonly reported were injection site pain, fatigue, headache, muscle ache and joint stiffness.

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