The International Severe Asthma Registry (ISAR) was established in 2017 to advance the understanding of severe asthma and its management, thereby improving patient care worldwide. As the first global registry for adults with severe asthma, ISAR enabled individual registries to standardize and pool their data, creating a comprehensive, harmonized dataset with sufficient statistical power to address key research questions and knowledge gaps. Today, ISAR is the largest repository of real-world data on severe asthma, curating data on nearly 35,000 patients from 28 countries worldwide, and has become a leading contributor to severe asthma research. Research using ISAR data has provided valuable insights on the characteristics of severe asthma, its burdens and risk factors, real-world treatment effectiveness, and barriers to specialist care, which are collectively informing improved asthma management. Besides changing clinical thinking via research, ISAR aims to advance real-world practice through initiatives that improve registry data quality and severe asthma care. In 2024, ISAR refined essential research variables to enhance data quality and launched a web-based data acquisition and reporting system (QISAR), which integrates data collection with clinical consultations and enables longitudinal data tracking at patient, center, and population levels. Quality improvement priorities include collecting standardized data during consultations and tracking and optimizing patient journeys via QISAR and integrating primary/secondary care pathways to expedite specialist severe asthma management and facilitate clinical trial recruitment. ISAR envisions a future in which timely specialist referral and initiation of biologic therapy can obviate long-term systemic corticosteroid use and enable more patients to achieve remission.

The International Severe Asthma Registry (ISAR) was established in 2017 to advance the understanding of severe asthma and its management, thereby improving patient care worldwide. As the first global registry for adults with severe asthma, ISAR enabled individual registries to standardize and pool their data, creating a comprehensive, harmonized dataset with sufficient statistical power to address key research questions and knowledge gaps. Today, ISAR is the largest repository of real-world data on severe asthma, curating data on nearly 35,000 patients from 28 countries worldwide, and has become a leading contributor to severe asthma research. Research using ISAR data has provided valuable insights on the characteristics of severe asthma, its burdens and risk factors, real-world treatment effectiveness, and barriers to specialist care, which are collectively informing improved asthma management. Besides changing clinical thinking via research, ISAR aims to advance real-world practice through initiatives that improve registry data quality and severe asthma care. In 2024, ISAR refined essential research variables to enhance data quality and launched a web-based data acquisition and reporting system (QISAR), which integrates data collection with clinical consultations and enables longitudinal data tracking at patient, center, and population levels. Quality improvement priorities include collecting standardized data during consultations and tracking and optimizing patient journeys via QISAR and integrating primary/secondary care pathways to expedite specialist severe asthma management and facilitate clinical trial recruitment. ISAR envisions a future in which timely specialist referral and initiation of biologic therapy can obviate long-term systemic corticosteroid use and enable more patients to achieve remission.

The International Severe Asthma Registry (ISAR) was established in 2017 to advance the understanding of severe asthma and its management, thereby improving patient care worldwide. As the first global registry for adults with severe asthma, ISAR enabled individual registries to standardize and pool their data, creating a comprehensive, harmonized dataset with sufficient statistical power to address key research questions and knowledge gaps. Today, ISAR is the largest repository of real-world data on severe asthma, curating data on nearly 35,000 patients from 28 countries worldwide, and has become a leading contributor to severe asthma research. Research using ISAR data has provided valuable insights on the characteristics of severe asthma, its burdens and risk factors, real-world treatment effectiveness, and barriers to specialist care, which are collectively informing improved asthma management. Besides changing clinical thinking via research, ISAR aims to advance real-world practice through initiatives that improve registry data quality and severe asthma care. In 2024, ISAR refined essential research variables to enhance data quality and launched a web-based data acquisition and reporting system (QISAR), which integrates data collection with clinical consultations and enables longitudinal data tracking at patient, center, and population levels. Quality improvement priorities include collecting standardized data during consultations and tracking and optimizing patient journeys via QISAR and integrating primary/secondary care pathways to expedite specialist severe asthma management and facilitate clinical trial recruitment. ISAR envisions a future in which timely specialist referral and initiation of biologic therapy can obviate long-term systemic corticosteroid use and enable more patients to achieve remission.

The International Severe Asthma Registry (ISAR) was established in 2017 to advance the understanding of severe asthma and its management, thereby improving patient care worldwide. As the first global registry for adults with severe asthma, ISAR enabled individual registries to standardize and pool their data, creating a comprehensive, harmonized dataset with sufficient statistical power to address key research questions and knowledge gaps. Today, ISAR is the largest repository of real-world data on severe asthma, curating data on nearly 35,000 patients from 28 countries worldwide, and has become a leading contributor to severe asthma research. Research using ISAR data has provided valuable insights on the characteristics of severe asthma, its burdens and risk factors, real-world treatment effectiveness, and barriers to specialist care, which are collectively informing improved asthma management. Besides changing clinical thinking via research, ISAR aims to advance real-world practice through initiatives that improve registry data quality and severe asthma care. In 2024, ISAR refined essential research variables to enhance data quality and launched a web-based data acquisition and reporting system (QISAR), which integrates data collection with clinical consultations and enables longitudinal data tracking at patient, center, and population levels. Quality improvement priorities include collecting standardized data during consultations and tracking and optimizing patient journeys via QISAR and integrating primary/secondary care pathways to expedite specialist severe asthma management and facilitate clinical trial recruitment. ISAR envisions a future in which timely specialist referral and initiation of biologic therapy can obviate long-term systemic corticosteroid use and enable more patients to achieve remission.

The International Severe Asthma Registry (ISAR) was established in 2017 to advance the understanding of severe asthma and its management, thereby improving patient care worldwide. As the first global registry for adults with severe asthma, ISAR enabled individual registries to standardize and pool their data, creating a comprehensive, harmonized dataset with sufficient statistical power to address key research questions and knowledge gaps. Today, ISAR is the largest repository of real-world data on severe asthma, curating data on nearly 35,000 patients from 28 countries worldwide, and has become a leading contributor to severe asthma research. Research using ISAR data has provided valuable insights on the characteristics of severe asthma, its burdens and risk factors, real-world treatment effectiveness, and barriers to specialist care, which are collectively informing improved asthma management. Besides changing clinical thinking via research, ISAR aims to advance real-world practice through initiatives that improve registry data quality and severe asthma care. In 2024, ISAR refined essential research variables to enhance data quality and launched a web-based data acquisition and reporting system (QISAR), which integrates data collection with clinical consultations and enables longitudinal data tracking at patient, center, and population levels. Quality improvement priorities include collecting standardized data during consultations and tracking and optimizing patient journeys via QISAR and integrating primary/secondary care pathways to expedite specialist severe asthma management and facilitate clinical trial recruitment. ISAR envisions a future in which timely specialist referral and initiation of biologic therapy can obviate long-term systemic corticosteroid use and enable more patients to achieve remission.

BACKGROUND: Compressive loading of bone causes hydrostatic pressure changes which have been proposed as an osteogenic differentiation stimulus for mesenchymal stem cells (hMSCs). We hypothesised that hMSCs are adapted to differentiate only in response to cyclic hydrostatic pressures above critical thresholds of magnitude and frequency which correspond to physiological levels of anabolic bone loading. METHODS: Using a pneumatic-hydrostatic bioreactor, we applied hydrostatic pressure regimes to human hMSCs in 3D collagen hydrogel cultures for 1 h/day over 28 days to determine which levels of pressure and frequency stimulated osteogenesis in vitro. RESULTS: Stimulation of the 3D cultures with 0–280 kPa cyclic hydrostatic pressure at 1 Hz resulted in up to 75% mineralisation in the hydrogel (without exogenous growth factors), whilst static culture or variations of the regime with either constant high pressure (280 kPa, 0 Hz), low-frequency (0.05 Hz, 280 kPa) or low-magnitude (70 kPa, 1 Hz) stimulation had no osteogenic effects ( 2% mineralisation). Nuclear translocation of YAP was observed following cyclic hydrostatic pressure in mature MLO-A5 osteoblasts but not in hMSCs, suggesting that cyclic hydrostatic pressure activates different mechanotransduction pathways in undifferentiated stem cells and committed osteoblasts. CONCLUSIONS Hydrostatic pressure is a potent stimulus for differentiating MSC into highly active osteoblasts and may therefore be a versatile tool for translational cell engineering. We have demonstrated that there are minimum levels of force and frequency needed to trigger osteogenesis, i.e. a pressure ‘switch’, which corresponds to the physiological forces experienced by cells in their native mesenchymal niche. The mechanotransduction mechanisms underpinning these effects are the subject of further study.

BACKGROUND: Compressive loading of bone causes hydrostatic pressure changes which have been proposed as an osteogenic differentiation stimulus for mesenchymal stem cells (hMSCs). We hypothesised that hMSCs are adapted to differentiate only in response to cyclic hydrostatic pressures above critical thresholds of magnitude and frequency which correspond to physiological levels of anabolic bone loading. METHODS: Using a pneumatic-hydrostatic bioreactor, we applied hydrostatic pressure regimes to human hMSCs in 3D collagen hydrogel cultures for 1 h/day over 28 days to determine which levels of pressure and frequency stimulated osteogenesis in vitro. RESULTS: Stimulation of the 3D cultures with 0–280 kPa cyclic hydrostatic pressure at 1 Hz resulted in up to 75% mineralisation in the hydrogel (without exogenous growth factors), whilst static culture or variations of the regime with either constant high pressure (280 kPa, 0 Hz), low-frequency (0.05 Hz, 280 kPa) or low-magnitude (70 kPa, 1 Hz) stimulation had no osteogenic effects ( 2% mineralisation). Nuclear translocation of YAP was observed following cyclic hydrostatic pressure in mature MLO-A5 osteoblasts but not in hMSCs, suggesting that cyclic hydrostatic pressure activates different mechanotransduction pathways in undifferentiated stem cells and committed osteoblasts. CONCLUSIONS Hydrostatic pressure is a potent stimulus for differentiating MSC into highly active osteoblasts and may therefore be a versatile tool for translational cell engineering. We have demonstrated that there are minimum levels of force and frequency needed to trigger osteogenesis, i.e. a pressure ‘switch’, which corresponds to the physiological forces experienced by cells in their native mesenchymal niche. The mechanotransduction mechanisms underpinning these effects are the subject of further study.

BACKGROUND: Compressive loading of bone causes hydrostatic pressure changes which have been proposed as an osteogenic differentiation stimulus for mesenchymal stem cells (hMSCs). We hypothesised that hMSCs are adapted to differentiate only in response to cyclic hydrostatic pressures above critical thresholds of magnitude and frequency which correspond to physiological levels of anabolic bone loading. METHODS: Using a pneumatic-hydrostatic bioreactor, we applied hydrostatic pressure regimes to human hMSCs in 3D collagen hydrogel cultures for 1 h/day over 28 days to determine which levels of pressure and frequency stimulated osteogenesis in vitro. RESULTS: Stimulation of the 3D cultures with 0–280 kPa cyclic hydrostatic pressure at 1 Hz resulted in up to 75% mineralisation in the hydrogel (without exogenous growth factors), whilst static culture or variations of the regime with either constant high pressure (280 kPa, 0 Hz), low-frequency (0.05 Hz, 280 kPa) or low-magnitude (70 kPa, 1 Hz) stimulation had no osteogenic effects ( 2% mineralisation). Nuclear translocation of YAP was observed following cyclic hydrostatic pressure in mature MLO-A5 osteoblasts but not in hMSCs, suggesting that cyclic hydrostatic pressure activates different mechanotransduction pathways in undifferentiated stem cells and committed osteoblasts. CONCLUSIONS Hydrostatic pressure is a potent stimulus for differentiating MSC into highly active osteoblasts and may therefore be a versatile tool for translational cell engineering. We have demonstrated that there are minimum levels of force and frequency needed to trigger osteogenesis, i.e. a pressure ‘switch’, which corresponds to the physiological forces experienced by cells in their native mesenchymal niche. The mechanotransduction mechanisms underpinning these effects are the subject of further study.

BACKGROUND: Compressive loading of bone causes hydrostatic pressure changes which have been proposed as an osteogenic differentiation stimulus for mesenchymal stem cells (hMSCs). We hypothesised that hMSCs are adapted to differentiate only in response to cyclic hydrostatic pressures above critical thresholds of magnitude and frequency which correspond to physiological levels of anabolic bone loading. METHODS: Using a pneumatic-hydrostatic bioreactor, we applied hydrostatic pressure regimes to human hMSCs in 3D collagen hydrogel cultures for 1 h/day over 28 days to determine which levels of pressure and frequency stimulated osteogenesis in vitro. RESULTS: Stimulation of the 3D cultures with 0–280 kPa cyclic hydrostatic pressure at 1 Hz resulted in up to 75% mineralisation in the hydrogel (without exogenous growth factors), whilst static culture or variations of the regime with either constant high pressure (280 kPa, 0 Hz), low-frequency (0.05 Hz, 280 kPa) or low-magnitude (70 kPa, 1 Hz) stimulation had no osteogenic effects ( 2% mineralisation). Nuclear translocation of YAP was observed following cyclic hydrostatic pressure in mature MLO-A5 osteoblasts but not in hMSCs, suggesting that cyclic hydrostatic pressure activates different mechanotransduction pathways in undifferentiated stem cells and committed osteoblasts. CONCLUSIONS Hydrostatic pressure is a potent stimulus for differentiating MSC into highly active osteoblasts and may therefore be a versatile tool for translational cell engineering. We have demonstrated that there are minimum levels of force and frequency needed to trigger osteogenesis, i.e. a pressure ‘switch’, which corresponds to the physiological forces experienced by cells in their native mesenchymal niche. The mechanotransduction mechanisms underpinning these effects are the subject of further study.

BACKGROUND: Compressive loading of bone causes hydrostatic pressure changes which have been proposed as an osteogenic differentiation stimulus for mesenchymal stem cells (hMSCs). We hypothesised that hMSCs are adapted to differentiate only in response to cyclic hydrostatic pressures above critical thresholds of magnitude and frequency which correspond to physiological levels of anabolic bone loading. METHODS: Using a pneumatic-hydrostatic bioreactor, we applied hydrostatic pressure regimes to human hMSCs in 3D collagen hydrogel cultures for 1 h/day over 28 days to determine which levels of pressure and frequency stimulated osteogenesis in vitro. RESULTS: Stimulation of the 3D cultures with 0–280 kPa cyclic hydrostatic pressure at 1 Hz resulted in up to 75% mineralisation in the hydrogel (without exogenous growth factors), whilst static culture or variations of the regime with either constant high pressure (280 kPa, 0 Hz), low-frequency (0.05 Hz, 280 kPa) or low-magnitude (70 kPa, 1 Hz) stimulation had no osteogenic effects ( 2% mineralisation). Nuclear translocation of YAP was observed following cyclic hydrostatic pressure in mature MLO-A5 osteoblasts but not in hMSCs, suggesting that cyclic hydrostatic pressure activates different mechanotransduction pathways in undifferentiated stem cells and committed osteoblasts. CONCLUSIONS Hydrostatic pressure is a potent stimulus for differentiating MSC into highly active osteoblasts and may therefore be a versatile tool for translational cell engineering. We have demonstrated that there are minimum levels of force and frequency needed to trigger osteogenesis, i.e. a pressure ‘switch’, which corresponds to the physiological forces experienced by cells in their native mesenchymal niche. The mechanotransduction mechanisms underpinning these effects are the subject of further study.