The AECOPD cohort will be hospitalized for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with respiratory failure requiring invasive or non-invasive mechanical ventilation. We will be following patients from admission through to discharge, and during a follow-up visit (~2 months from discharge). During the follow-up visit we will be administering 60mg of methylprednisolone once to study possible steroid resistance.

The Stable COPD cohort will not have had an AECOPD within the past 6 months and will be frequency matched to the AECOPD cohort. The Stable COPD cohort will have one research visit where we will administer 60mg of methylprednisolone once to study possible steroid resistance.

Collection of whole blood, serum, plasma, PBMCs, urine, nasal cells, and microbiome from the mouth, sinonasal passage, lung and stool.

COPD

Emphysema or COPD

COPD Exacerbation

COPD Exacerbation Acute

Respiratory Failure

Ventilatory Failure

1. Methylprednisolone is a steroid (corticosteroid) similar to a product produced in the adrenal glands. It is used to help relieve inflammation (swelling, heat, redness, and pain) and is used to treat certain medical issues including COPD.

Methylprednisolone

University of Colorado Denver

Steroid Resistance During COPD Exacerbations With Respiratory Failure

Targeting Steroid Resistance During Acute Exacerbations of Chronic Obstructive Pulmonary Disease With Respiratory Failure - The AECOPD Resistance Study

The ability of methylprednisolone to suppress interleukin-8 (IL-8) release from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs).

Baseline expression and induction of Dual Specificity Phosphatase 1 (DUSP1) in peripheral blood monocytes from patients recently admitted with an acute exacerbation of chronic obstructive pulmonary disease with respiratory failure versus stable, matched controls.

Differences in Mitogen-activated Protein (MAP) Kinase Pathway activity in peripheral blood monocytes from patients recently admitted with an acute exacerbation of chronic obstructive pulmonary disease with respiratory failure versus stable, matched controls.

Baseline expression and induction of Glucocorticoid-induced Leucine Zipper (GILZ) and DUSP isoforms in peripheral blood monocytes from patients recently admitted with an acute exacerbation of chronic obstructive pulmonary disease with respiratory failure versus stable, matched controls.

The role of HDAC2 in steroid resistance will be examined by measuring HDAC2 expression and histone transacetylase and deacetylase activity in PBMCs.

Measuring methylprednisolone pharmacokinetics in patients following an acute exacerbation of COPD with respiratory failure versus a stable, matched control.

Ribonucleic acid (RNA) sequencing will be performed on PBMCs from patients and controls before and after exposure to methylprednisolone.

University of Colorado, Denver

National Jewish Health

Each patient will undergo mastectomy(ies) if immediate reconstruction is being performed, followed by uni- or bilateral abdominally based free flap harvest, microsurgical anastomoses, and flap inset. If randomized to the ketorolac intervention group, then the participant will receive 30 mg of intravenous (IV) ketorolac tromethamine. The anaesthetist will give participants their first study drug intravenously at the conclusion of surgery. The participant will then continue to receive their assigned drug every 6 hours for 72 hours, for a total of 13 doses. Patients all receive 1:1 care from nursing staff in the early postoperative period, and their nurse will administer all drugs given on the surgical ward.

Each patient will undergo mastectomy(ies) if immediate reconstruction is being performed, followed by uni- or bilateral abdominally based free flap harvest, microsurgical anastomoses, and flap inset. If randomized to the control group the patient will be given a sham IV medication. The sham medication will be normal saline at the same volume as ketorolac, which corresponds to 3 ccs. The anaesthetist will give participants their first study drug intravenously at the conclusion of surgery. The participant will then continue to receive their assigned drug every 6 hours for 72 hours, for a total of 13 doses. Patients all receive 1:1 care from nursing staff in the early postoperative period, and their nurse will administer all drugs given on the surgical ward.

Breast Cancer Female

Ketorolac Tromethamine

Normal Saline

Ketorolac for Analgesia followiNG Autologous Breast RecOnstructiOn

recorded in days beginning post operative day number one

Total narcotic consumption over first 72 hours converted to morphine equivalence

Total surgical drain output over first 72 hours

Any hematoma requiring management in the operating room

Any infection requiring antibiotics, or flap complications requiring management in the operating room

Joey Corkum

Physician

Nova Scotia Health Authority

Patients with Hypophosphatasia disease or high-grade suspicion for Hypophosphatasia disease

For the development of the new biomarkers using the technique of Mass-spectrometry 7, 5 ml EDTA blood and a dry blood spot filter card are taken. To proof the correct di- agnosis of Hypophosphatasia in those patients where up to the enrollment in the study no genetic testing has been done, sequencing of Hypophosphatasia disease will be done. The analyses will be done at the: Centogene AG Am Strande 7 18055 Rostock Germany

Defective Mineralization

Centogene is one of the leading laboratories focusing on genetic testing for rare hereditary disorders. We now offer more than 2200 routine genetic and biochemical tests.

Centogene AG

NIRMAN Navi Mumbai Institute of Research In Mental And Neurological Handicap/Pediatric Geneticist

Lady Ridgeway Hospital for Children

Biomarker for Hypophosphatasia Disease (BioHypophos)

Biomarker for Hypophosphatasia Disease AN INTERNATIONAL, MULTICENTER, EPIDEMIOLOGICAL PROTOCOL

Next-Generation Sequencing (NGS) of the ALPL gene will be performed. The mutation will be confirmed by Sanger sequencing.

The quantitative determination of small molecules (molecular weight 150-700 kD, given as ng/μl) within a dried blood spot sample will be validated via liquid chromatography multiple reaction-monitoring mass spectrometry (LC/MRM-MS) and compared with a merged control cohort. The statistically best validated molecule will be considered as a disease specific biomarker.

Centogene AG Rostock

3 HPP patients are to be enrolled in Cohort 1 and receive a single IV dose and three weekly SC doses of Asfotase Alfa . End of Study for patients in Cohort 1 is at 8 weeks.

Cohort 2 will begin when the safety and PK data for Cohort 1 weeks 1-4 has been reviewed by the DSMB. Cohort 2 will enroll 3 HPP patients and will receive a higher dose level than Cohort 1. Cohort 2 patients will have a single IV dose and three weekly SC doses of Asfotase Alfa . End of Study for patients in Cohort 2 is at 8 weeks.

Hypophosphatasia (HPP)

The initial IV dose to be administered to patients was set at one-tenth the no adverse effect level (NOAEL) as determined by one month toxicology studies in animals in which Asfotase Alfa was administered as a single weekly IV dose. The SC doses to be administered are lower than the IV doses and are thought to be near or at the anticipated daily efficacious dose. Dosing will be as follows:
Cohort 1: In Week 1, patients will receive an IV infusion of Asfotase Alfa at a dose of 3 mg/kg. In Weeks 2, 3 and 4, patients will receive weekly SC injections of Asfotase Alfa at a dose of 1 mg/kg SC.

Asfotase Alfa

Cohort 2: In Week 1, patients will receive an IV infusion of Asfotase Alfa at a dose of 7 mg/kg. In Weeks 2, 3 and 4, patients will receive weekly SC injections of Asfotase Alfa at a dose of 1.5 mg/kg SC.

Hypophosphatasia Website for Healthcare Providers

Yahoo health group for HPP with an international list serve where patients can correspond and post questions to the group

Barnes Jewish Hospital- Washington University School of Medicine

Duke University Medical Center

Department of Pediatrics & Child Health, Health Sciences Centre Winnipeg, University of Manitoba

Safety Study of Human Recombinant Tissue Non-Specific Alkaline Phosphatase Fusion Protein Asfotase Alfa in Adults With Hypophosphatasia (HPP)

A Multicenter, Open-Label, Dose Escalating Study of the Safety, Tolerability and Pharmacology of Human Recombinant Tissue Non-Specific Alkaline Phosphatase Fusion Protein Asfotase Alfa in Adults With Hypophosphatasia (HPP)

respiratory insufficiency/phosphatase

Steroid Resistance During COPD Exacerbations With Respiratory Failure

Ketorolac for Analgesia followiNG Autologous Breast RecOnstructiOn

Biomarker for Hypophosphatasia Disease (BioHypophos)

Safety Study of Human Recombinant Tissue Non-Specific Alkaline Phosphatase Fusion Protein Asfotase Alfa in Adults With Hypophosphatasia (HPP)

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