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1. Anisotropic mechanosensitive pathways in the diaphragm and their implications in muscular dystrophies

   https://doi.org/10.1007/s10974-017-9483-7  

   Pardo, Patricia S.; Lopez, Michael A.; Mohamed, Junaith S.; Boriek, Aladin M. (October 2017, Journal of Muscle Research and Cell Motility)

   The diaphragm is the "respiratory pump;" the muscle that generates pressure to allow ventilation. Diaphragm muscles play a vital function and thus are subjected to continuous mechanical loading. One of its peculiarities is the ability to generate distinct mechanical and biochemical responses depending on the direction through which the mechanical forces applied to it. Contractile forces originated from its contractile components are transmitted to other structural components of its muscle fibers and the surrounding connective tissue. The anisotropic mechanical properties of the diaphragm are translated into biochemical signals that are directionally mechanosensitive by mechanisms that appear to be unique to this muscle. Here, we reviewed the current state of knowledge on the biochemical pathways regulated by mechanical signals emphasizing their anisotropic behavior in the normal diaphragm and analyzed how they are affected in muscular dystrophies. 

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2. Rule-Based Cohort Definitions for Acute Respiratory Failure: Electronic Phenotyping Algorithm

   https://doi.org/10.2196/18402  

   Essay, Patrick; Mosier, Jarrod; Subbian, Vignesh (January 2020, JMIR Medical Informatics)

   Background Acute respiratory failure is generally treated with invasive mechanical ventilation or noninvasive respiratory support strategies. The efficacies of the various strategies are not fully understood. There is a need for accurate therapy-based phenotyping for secondary analyses of electronic health record data to answer research questions regarding respiratory management and outcomes with each strategy. Objective The objective of this study was to address knowledge gaps related to ventilation therapy strategies across diverse patient populations by developing an algorithm for accurate identification of patients with acute respiratory failure. To accomplish this objective, our goal was to develop rule-based computable phenotypes for patients with acute respiratory failure using remotely monitored intensive care unit (tele-ICU) data. This approach permits analyses by ventilation strategy across broad patient populations of interest with the ability to sub-phenotype as research questions require. Methods Tele-ICU data from ≥200 hospitals were used to create a rule-based algorithm for phenotyping patients with acute respiratory failure, defined as an adult patient requiring invasive mechanical ventilation or a noninvasive strategy. The dataset spans a wide range of hospitals and ICU types across all US regions. Structured clinical data, including ventilation therapy start and stop times, medication records, and nurse and respiratory therapy charts, were used to define clinical phenotypes. All adult patients of any diagnoses with record of ventilation therapy were included. Patients were categorized by ventilation type, and analysis of event sequences using record timestamps defined each phenotype. Manual validation was performed on 5% of patients in each phenotype. Results We developed 7 phenotypes: (0) invasive mechanical ventilation, (1) noninvasive positive-pressure ventilation, (2) high-flow nasal insufflation, (3) noninvasive positive-pressure ventilation subsequently requiring intubation, (4) high-flow nasal insufflation subsequently requiring intubation, (5) invasive mechanical ventilation with extubation to noninvasive positive-pressure ventilation, and (6) invasive mechanical ventilation with extubation to high-flow nasal insufflation. A total of 27,734 patients met our phenotype criteria and were categorized into these ventilation subgroups. Manual validation of a random selection of 5% of records from each phenotype resulted in a total accuracy of 88% and a precision and recall of 0.8789 and 0.8785, respectively, across all phenotypes. Individual phenotype validation showed that the algorithm categorizes patients particularly well but has challenges with patients that require ≥2 management strategies. Conclusions Our proposed computable phenotyping algorithm for patients with acute respiratory failure effectively identifies patients for therapy-focused research regardless of admission diagnosis or comorbidities and allows for management strategy comparisons across populations of interest. 

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3. Mechano-Signal Transduction Pathways of the Diaphragmatic Muscle and Role of Cytoskeleton

   https://doi.org/10.3390/genes16080968  

   Mohamed, Junaith S; Pardo, Patricia S; Boriek, Aladin M (August 2025, Genes)

   Mechanotransduction, also referred to as mechano-signal transduction, is a biophysical process wherein cells perceive and respond to mechanical stimuli by converting them into biochemical signals that initiate specific cellular responses. This mechanism is fundamental to the development and growth, and proper functioning of mechanically active tissues, such as the diaphragm—a respiratory muscle vital for breathing in mammals. In vivo, the diaphragm is subjected to transdiaphragmatic pressure, and therefore, its muscle fibers are subjected to mechanical forces not only in the direction of the muscle fibers but also in the direction transverse to the fibers. Previous research conducted in our laboratory uncovered that stretching the diaphragm in either the longitudinal or transverse direction activates distinct mechanotransduction pathways. This indicates that signaling pathways in the diaphragm muscle are regulated in an anisotropic manner. In this review paper, we discussed the underlying mechanisms that regulate the anisotropic signaling pathways in the diaphragmatic muscle, emphasizing the mechanical role of cytoskeletal proteins in this context. Furthermore, we explored the regulatory mechanisms governing mechanosensitive gene transcription, including microRNAs (mechanomiRs), within the diaphragm muscle. Finally, we examined potential links between anisotropic signaling in the diaphragm muscle and various skeletal muscle disorders. 

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4. Mechanical Power and Ventilator-induced Lung Injury: What Does Physics Have to Say?

   https://doi.org/10.1164/rccm.202307-1292VP  

   Bates, Jason H.T.; Kaczka, David W.; Kollisch-Singule, Michaela; Nieman, Gary F; Gaver III, Donald P (September 2023, American Journal of Respiratory and Critical Care Medicine)

   Ventilator-induced lung injury (VILI) is a potential threat to anyone receiving supportive mechanical ventilation for acute respiratory failure. Despite decades of research, however, the safest way to ventilate any given patient remains controversial. This makes fertile ground for novel concepts, and one that has arisen recently concerns the idea that a ventilator imparts potentially damaging mechanical energy to the lungs. The motivation for this concept is clear: energy transfer is involved when any structure becomes physically damaged. It may be intuitive, then, that the rate at which energy is delivered to the lungs by a ventilator, namely mechanical power, should be associated with VILI. Nevertheless, understanding the relationship between mechanical power and VILI requires clarity on the difference between stored versus dissipated energy regardless of whether ventilation is caused by positive pressure at the airway opening or negative pressure in the pleural space. 

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5. Ratchet recruitment in the acute respiratory distress syndrome: lessons from the newborn cry

   https://doi.org/10.3389/fphys.2023.1287416  

   Nieman, Gary F.; Herrmann, Jacob; Satalin, Joshua; Kollisch-Singule, Michaela; Andrews, Penny L.; Habashi, Nader M.; Tingay, David G.; Gaver, Donald P.; Bates, Jason H.; Kaczka, David W. (November 2023, Frontiers in Physiology)

   Alysson Roncally Silva Carvalho (Ed.)

   Patients with acute respiratory distress syndrome (ARDS) have few treatment options other than supportive mechanical ventilation. The mortality associated with ARDS remains unacceptably high, and mechanical ventilation itself has the potential to increase mortality further by unintended ventilator-induced lung injury (VILI). Thus, there is motivation to improve management of ventilation in patients with ARDS. The immediate goal of mechanical ventilation in ARDS should be to prevent atelectrauma resulting from repetitive alveolar collapse and reopening. However, a long-term goal should be to re-open collapsed and edematous regions of the lung and reduce regions of high mechanical stress that lead to regional volutrauma. In this paper, we consider the proposed strategy used by the full-term newborn to open the fluid-filled lung during the initial breaths of life, by ratcheting tissues opened over a series of initial breaths with brief expirations. The newborn’s cry after birth shares key similarities with the Airway Pressure Release Ventilation (APRV) modality, in which the expiratory duration is sufficiently short to minimize end-expiratory derecruitment. Using a simple computational model of the injured lung, we demonstrate that APRV can slowly open even the most recalcitrant alveoli with extended periods of high inspiratory pressure, while reducing alveolar re-collapse with brief expirations. These processes together comprise a ratchet mechanism by which the lung is progressively recruited, similar to the manner in which the newborn lung is aerated during a series of cries, albeit over longer time scales. 

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