Microstructure-based modeling of primary cilia mechanics.

A primary cilium, made of nine microtubule doublets enclosed in a cilium membrane, is a mechanosensing organelle that bends under an external mechanical load and sends an intracellular signal through transmembrane proteins activated by cilium bending. The nine microtubule doublets are the main load-bearing structural component, while the transmembrane proteins on the cilium membrane are the main sensing component. No distinction was made between these two components in all existing models, where the stress calculated from the structural component (nine microtubule doublets) was used to explain the sensing location, which may be totally misleading. For the first time, we developed a microstructure-based primary cilium model by considering these two components separately. First, we refined the analytical solution of bending an orthotropic cylindrical shell for individual microtubule, and obtained excellent agreement between finite element simulations and the theoretical predictions of a microtubule bending as a validation of the structural component in the model. Second, by integrating the cilium membrane with nine microtubule doublets and simulating the tip-anchored optical tweezer experiment on our computational model, we found that the microtubule doublets may twist significantly as the whole cilium bends. Third, besides being cilium-length-dependent, we found the mechanical properties of the cilium are also highly deformation-dependent. More important, we found that the cilium membrane near the base is not under pure in-plane tension or compression as previously thought, but has significant local bending stress. This challenges the traditional model of cilium mechanosensing, indicating that transmembrane proteins may be activated more by membrane curvature than membrane stretching. Finally, we incorporated imaging data of primary cilia into our microstructure-based cilium model, and found that comparing to the ideal model with uniform microtubule length, the imaging-informed model shows the nine microtubule doublets interact more evenly with the cilium membrane, and their contact locations can cause even higher bending curvature in the cilium membrane than near the base.

Microstructure-Based Modeling of Primary Cilia Mechanics.

A primary cilium, made of nine microtubule doublets enclosed in a cilium membrane, is a mechanosensing organelle that bends under an external mechanical load and sends an intracellular signal through transmembrane proteins activated by cilium bending. The nine microtubule doublets are the main load-bearing structural component, while the transmembrane proteins on the cilium membrane are the main sensing component. No distinction was made between these two components in all existing models, where the stress calculated from the structural component (nine microtubule doublets) was used to explain the sensing location, which may be totally misleading. For the first time, we developed a microstructure-based primary cilium model by considering these two components separately. First, we refined the analytical solution of bending an orthotropic cylindrical shell for individual microtubule, and obtained excellent agreement between finite element simulations and the theoretical predictions of a microtubule bending as a validation of the structural component in the model. Second, by integrating the cilium membrane with nine microtubule doublets, we found that the microtubule doublets may twist significantly as the whole cilium bends. Third, besides being cilium-length-dependent, we found the mechanical properties of the cilium are also highly deformation-dependent. More important, we found that the cilium membrane near the base is not under pure in-plane tension or compression as previously thought, but has significant local bending stress. This challenges the traditional model of cilium mechanosensing, indicating that transmembrane proteins may be activated more by membrane curvature than membrane stretching. Finally, we incorporated imaging data of primary cilia into our microstructure-based cilium model, and found that comparing to the ideal model with uniform microtubule length, the imaging-informed model shows the nine microtubule doublets interact more evenly with the cilium membrane, and their contact locations can cause even higher bending curvature in the cilium membrane than near the base. SIGNIFICANCE: Factors regulating the mechanical response of a primary cilium to fluid flow remain unclear. Modeling the microtubule doublet as a composite of two orthotropic shells and the ciliary axoneme as an elastic shell enclosing nine such microtubule doublets, we found that the length distribution of microtubule doublets (inferred from cryogenic electron tomography images) is the primary determining factor in the bending stiffness of primary cilia, rather than just the ciliary length. This implies ciliary-associated transmembrane proteins may be activated by membrane curvature changes rather than just membrane stretching. These insights challenge the traditional view of ciliary mechanosensation and expands our understanding of the different ways in which cells perceive and respond to mechanical stimuli.

Fluid-structure interaction modelling of neighboring tubes with primary cilium analysis.

We have developed a numerical model of two osculating cylindrical elastic renal tubules to investigate the impact of neighboring tubules on the stress applied to a primary cilium. We hypothesize that the stress at the base of the primary cilium will depend on the mechanical coupling of the tubules due to local constrained motion of the tubule wall. The objective of this work was to determine the in-plane stresses of a primary cilium attached to the inner wall of one renal tubule subject to the applied pulsatile flow, with a neighboring renal tube filled with stagnant fluid in close proximity to the primary tubule. We used the commercial software COMSOLⓇ to model the fluid-structure interaction of the applied flow and tubule wall, and we applied a boundary load to the face of the primary cilium during this simulation to produces a stress at its base. We confirm our hypothesis by observing that on average the in-plane stresses are greater at the base of the cilium when there is a neighboring renal tube versus if there is no neighboring tube at all. In combination with the hypothesized function of a cilium as a biological fluid flow sensor, these results indicate that flow signaling may also depend on how the tubule wall is constrained by neighboring tubules. Our results may be limited in their interpretation due to the simplified nature of our model geometry, and further improvements to the model may potentially lead to the design of future experiments.

Dihydroceramide desaturase 1 (DES1) promotes anchorage-independent survival downstream of HER2-driven glucose uptake and metabolism.

Oncogenic reprogramming of cellular metabolism is a hallmark of many cancers, but our mechanistic understanding of how such dysregulation is linked to tumor behavior remains poor. In this study, we have identified dihydroceramide desaturase (DES1)-which catalyzes the last step in de novo sphingolipid synthesis-as necessary for the acquisition of anchorage-independent survival (AIS), a key cancer enabling biology, and establish DES1 as a downstream effector of HER2-driven glucose uptake and metabolism. We further show that DES1 is sufficient to drive AIS and in vitro tumorigenicity and that increased DES1 levels-found in a third of HER2+ breast cancers-are associated with worse survival outcomes. Taken together, our findings reveal a novel pro-tumor role for DES1 as a transducer of HER2-driven glucose metabolic signals and provide evidence that targeting DES1 is an effective approach for overcoming AIS. Results further suggest that DES1 may have utility as a biomarker of aggressive and metastasis-prone HER2+ breast cancer.

Association of measured quality with financial health among U.S. hospitals.

BACKGROUND: High-quality care is a clear objective for hospital leaders, but hospitals must balance investing in quality with financial stability. Poor hospital financial health can precipitate closure, limiting patients' access to care. Whether hospital quality is associated with financial health remains poorly understood. The objective of this study was to compare financial performance at high-quality and low-quality hospitals. METHODS: We performed a retrospective observational cohort study of U.S. hospitals using the American Hospital Association and Hospital Compare datasets for years 2013 to 2018. We used multilevel mixed-effects linear and logistic regression models with fixed year effects and random intercepts for hospitals to identify associations between hospitals' measured quality outcomes-30-day hospital-wide readmission rate and the patient safety indicator-90 (PSI-90)-and their financial margins and risk of financial distress in the same year and the subsequent year. Our sample included 20,919 observations from 4,331 unique hospitals. RESULTS: In 2018, the median 30-day readmission rate was 15.2 (interquartile range [IQR] 14.8-15.6), the median PSI-90 score was 0.96 (IQR 0.89-1.07), the median operating margin was -1.8 (IQR -9.7-5.9), and 750 (22.7%) hospitals experienced financial distress. Hospitals in the best quintile of readmission rates experienced higher operating margins (+0.95%, 95% CI [0.51-1.39], p < .001) and lower odds of distress (odds ratio [OR] 0.56, 95% CI [0.45-0.70], p < .001) in the same year as compared to hospitals in the worst quintile. Hospitals in the best quintile of PSI-90 had higher operating margins (+0.62%, 95% CI [0.17-1.08], p = .007) and lower odds of financial distress (OR 0.70, 95% CI [0.55-0.89], p = .003) as compared to hospitals in the worst quintile. The results were qualitatively similar for the same-year and lag-year analyses. CONCLUSION: Hospitals that deliver high-quality outcomes may experience superior financial performance compared to hospitals with poor-quality outcomes.

Cluster of Burkholderia cepacia Complex Infections Associated With Extracorporeal Membrane Oxygenation Water Heater Devices.

BACKGROUND: Burkholderia cepacia complex is a group of potential nosocomial pathogens often linked to contaminated water. We report on a cluster of 8 B. cepacia complex infections in cardiothoracic intensive care unit patients, which were attributed to contaminated extracorporeal membrane oxygenation (ECMO) water heaters. METHODS: In December 2020, we identified an increase in B. cepacia complex infections in the cardiothoracic intensive care unit at Brigham and Women's Hospital. We sought commonalities, sequenced isolates, obtained environmental specimens, and enacted mitigation measures. RESULTS: Whole-genome sequencing of 13 B. cepacia complex clinical specimens between November 2020 and February 2021 identified 6 clonally related isolates, speciated as Burkholderia contaminans. All 6 occurred in patients on ECMO. Microbiology review identified 2 additional B. contaminans cases from June 2020 that may have also been cluster related, including 1 in a patient receiving ECMO. All 8 definite or probable cluster cases required treatment; 3 patients died, and 3 experienced recurrent infections. After ECMO was identified as the major commonality, all 9 of the hospital's ECMO water heaters were cultured, and B. contaminans grew in all cultures. Cultures from air sampled adjacent to the water heaters were negative. Water heater touch screens were culture positive for B. contaminans, and the sink drain in the ECMO heater reprocessing room also grew clonal B. contaminans. Observations of reprocessing revealed opportunities for cross-contamination between devices through splashing from the contaminated sink. The cluster was aborted by removing all water heaters from clinical service. CONCLUSIONS: We identified a cluster of 8 B. cepacia complex infections associated with contaminated ECMO water heaters. This cluster underscores the potential risks associated with water-based ECMO heaters and, more broadly, water-based care for vulnerable patients.

Physics of martial arts: Incorporation of angular momentum to model body motion and strikes.

We develop a physics-based kinematic model of martial arts movements incorporating rotation and angular momentum, extending prior analyses. Here, our approach is designed for a classroom environment; we begin with a warm-up exercise introducing counter-intuitive aspects of rotational motion before proceeding to a set of model collision problems that are applied to martial arts movements. Finally, we develop a deformable solid-body mechanics model of a martial arts practitioner suitable for an intermediate mechanics course. We provide evidence for our improved model based on calculations from biomechanical data obtained from prior reports as well as time-lapse images of several different kicks. In addition to incorporating angular motion, our model explicitly makes reference to friction between foot and ground as an action-reaction pair, showing that this interaction provides the motive force/torque for nearly all martial arts movements. Moment-of-inertia tensors are developed to describe kicking movements and show that kicks aimed high, towards the head, transfer more momentum to the target than kicks aimed lower, e.g. towards the body.

Defining the Value of Interventional Radiology to Healthcare Stakeholders: Proceedings from a Society of Interventional Radiology Research Consensus Panel.

Interventional radiology (IR) has collectively struggled to articulate and prove its value to several external stakeholders. The goal of this research consensus panel was to provide a summary of the existing knowledge, identify current gaps in knowledge, identify the strengths and weaknesses in existing data, and prioritize research needs related to the value of IR. Panelists were asked to identify the critical relationships/alliances that should be fostered to advance the prioritized research and determine how the Society of Interventional Radiology and the Society of Interventional Radiology Foundation can further support these initiatives. Following presentations and discussions, it was determined that proving and quantifying how IR decreases the length of stay and prevents hospital admissions are the most salient, value-related research topics to pursue for the specialty.

Examining the Temperature Dependence of Louche Formation in Absinthe.

Absinthe is an anise-flavored alcohol that is typically served by adding cold water to form a cloudy green louche, similar to the cloudy white louche of ouzo. This microemulsion formation, due to the competing interactions within the oil-alcohol-water system, has been termed the ouzo effect. Previous work has examined the ternary oil-alcohol-water phase diagram in ouzo and limoncello. Additional work has also characterized the droplet size and stability of microemulsions in ouzo, limoncello, and pastis. However, less work has been done to examine the effect of temperature on louche formation despite the fact that the louche is traditionally formed by adding ice cold water. This work demonstrates that both the maximum turbidity and the fraction of alcohol at maximum turbidity are temperature-dependent. The louche formation can be fit with a logistic curve, and the resulting fit parameters are linear with temperature. Optical images show that the increased turbidity correlates with an increase in the number of droplets in the microemulsion.

Primary cilium: a paradigm for integrating mathematical modeling with experiments and numerical simulations in mechanobiology.

Primary cilia are non-motile, solitary (one per cell) microtubule-based organelles that emerge from the mother centriole after cells have exited the mitotic cycle. Identified as a mechanosensing organelle that responds to both mechanical and chemical stimuli, the primary cilium provides a fertile ground for integrative investigations of mathematical modeling, numerical simulations, and experiments. Recent experimental findings revealed considerable complexity to the underlying mechanosensory mechanisms that transmit extracellular stimuli to intracellular signaling many of which include primary cilia. In this invited review, we provide a brief survey of experimental findings on primary cilia and how these results lead to various mathematical models of the mechanics of the primary cilium bent under an external forcing such as a fluid flow or a trap. Mathematical modeling of the primary cilium as a fluid-structure interaction problem highlights the importance of basal anchorage and the anisotropic moduli of the microtubules. As theoretical modeling and numerical simulations progress, along with improved state-of-the-art experiments on primary cilia, we hope that details of ciliary regulated mechano-chemical signaling dynamics in cellular physiology will be understood in the near future.

A SARS-CoV-2 Cluster in an Acute Care Hospital.

BACKGROUND: Little is known about clusters of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in acute care hospitals. OBJECTIVE: To describe the detection, mitigation, and analysis of a large cluster of SARS-CoV-2 infections in an acute care hospital with mature infection control policies. DESIGN: Descriptive study. SETTING: Brigham and Women's Hospital, Boston, Massachusetts. PARTICIPANTS: Patients and staff with cluster-related SARS-CoV-2 infections. INTERVENTION: Close contacts of infected patients and staff were identified and tested every 3 days, patients on affected units were preemptively isolated and repeatedly tested, affected units were cleaned, room ventilation was measured, and specimens were sent for whole-genome sequencing. A case-control study was done to compare clinical interactions, personal protective equipment use, and breakroom and workroom practices in SARS-CoV-2-positive versus negative staff. MEASUREMENTS: Description of the cluster, mitigation activities, and risk factor analysis. RESULTS: Fourteen patients and 38 staff members were included in the cluster per whole-genome sequencing and epidemiologic associations. The index case was a symptomatic patient in whom isolation was discontinued after 2 negative results on nasopharyngeal polymerase chain reaction testing. The patient subsequently infected multiple roommates and staff, who then infected others. Seven of 52 (13%) secondary infections were detected only on second or subsequent tests. Eight of 9 (89%) patients who shared rooms with potentially contagious patients became infected. Potential contributing factors included high viral loads, nebulization, and positive pressure in the index patient's room. Risk factors for transmission to staff included presence during nebulization, caring for patients with dyspnea or cough, lack of eye protection, at least 15 minutes of exposure to case patients, and interactions with SARS-CoV-2-positive staff in clinical areas. Whole-genome sequencing confirmed that 2 staff members were infected despite wearing surgical masks and eye protection. LIMITATION: Findings may not be generalizable. CONCLUSION: SARS-CoV-2 clusters can occur in hospitals despite robust infection control policies. Insights from this cluster may inform additional measures to protect patients and staff. PRIMARY FUNDING SOURCE: None.

Sources of exposure identified through structured interviews of healthcare workers who test positive for severe acute respiratory coronavirus virus 2 (SARS-CoV-2): A prospective analysis at two teaching hospitals.

We interviewed 1,208 healthcare workers with positive SARS-CoV-2 tests between October 2020 and June 2021 to determine likely exposure sources. Overall, 689 (57.0%) had community exposures (479 from household members), 76 (6.3%) had hospital exposures (64 from other employees including 49 despite masking), 11 (0.9%) had community and hospital exposures, and 432 (35.8%) had no identifiable source of exposure.

Low Risk of Coronavirus Disease 2019 (COVID-19) Among Patients Exposed to Infected Healthcare Workers.

Many patients are fearful of acquiring coronavirus disease 2019 (COVID-19) in hospitals and clinics. We characterized the risk of COVID-19 among 226 patients exposed to healthcare workers with confirmed COVID-19. One patient may have been infected, suggesting that the risk of COVID-19 transmission from healthcare workers to patients is generally low.

Erector spinae plane block with catheter for management of percutaneous nephrolithotomy: A three case report.

INTRODUCTION: Percutaneous nephrolithotomy is a procedure used for management of refractory renal calculi. Oral and parenteral opioids, along with local anesthetic infiltration, neuraxial anesthesia, and paravertebral blocks are the most common methods of managing intra-operative and post-operative pain for these patients. The erector spinae plane block with catheter (ESPC) is a newer interfascial regional anesthetic technique that can be used to manage peri-operative pain in these patients. CLINICAL FINDINGS: Three patients complained of significant flank pain were scheduled for percutaneous nephrolithotomy under general anesthesia in the prone position. DIAGNOSES: Patients were diagnosed with large renal calculi. THERAPEUTIC INTERVENTIONS: Patients received ESPC in the pre-operative holding area at the level of the T7 transverse process. The ESPCS were bolused with a solution of 30 mL 0.25% bupivacaine with 4 mg dexamethasone prior to surgery. Patients also received oral tramadol 50 mg and acetaminophen 1 g as part of the multimodal pain protocol prior to surgery. After the procedure, the patients were bolused with 0.25% bupivacaine or started on an infusion of 0.25% bupivacaine to manage their pain. OUTCOMES: No opioid or other pain medications, other than the local anesthetic solution given in the ESPCs, were used during the intra-operative or post-operative period for management of pain in these patients. Visual analogue scale (VAS) scores were below 4 for all patients in the post-operative period, and patients did not report any issues with post-operative nausea or vomiting. CONCLUSION: These patients were compared to 3 prior patients who had undergone percutaneous nephrolithotomy without ESPC. The 3 patients without ESPC placement reported increased VAS scores, had increased opioid/pain medication consumption intraoperatively and postoperatively, and had increased incidence of perioperative nausea when compared to our ESPC patients. Our report shows that ESPC, in combination with a multimodal pain protocol, can be a good option for management of patients undergoing percutaneous nephrolithotomy.

Incidence of Nosocomial COVID-19 in Patients Hospitalized at a Large US Academic Medical Center.

Importance: Some patients are avoiding essential care for fear of contracting coronavirus disease 2019 (COVID-19) in hospitals. There are few data, however, on the risk of acquiring COVID-19 in US hospitals. Objective: To assess the incidence of COVID-19 among patients hospitalized at a large US academic medical center in the 12 weeks after the first inpatient case was identified. Design, Setting, and Participants: This cohort study included all patients admitted to Brigham and Women's Hospital (Boston, Massachusetts) between March 7 and May 30, 2020. Follow-up occurred through June 17, 2020. Medical records for all patients who first tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse-transcription polymerase chain reaction (RT-PCR) on hospital day 3 or later or within 14 days of discharge were reviewed. Exposures: A comprehensive infection control program was implemented that included dedicated COVID-19 units with airborne infection isolation rooms, personal protective equipment in accordance with US Centers for Disease Control and Prevention recommendations, personal protective equipment donning and doffing monitors, universal masking, restriction of visitors, and liberal RT-PCR testing of symptomatic and asymptomatic patients. Main Outcomes and Measures: Whether infection was community or hospital acquired based on timing of tests, clinical course, and exposures. Results: Over the 12-week period, 9149 patients (mean [SD] age, 46.1 [26.4] years; median [IQR] age, 51 years [30-67 years]; 5243 female [57.3%]) were admitted to the hospital, for whom 7394 SARS-CoV-2 RT-PCR tests were performed; 697 COVID-19 cases were confirmed, translating into 8656 days of COVID-19-related care. Twelve of the 697 hospitalized patients with COVID-19 (1.7%) first tested positive on hospital day 3 or later (median, 4 days; range, 3-15 days). Of these, only 1 case was deemed to be hospital acquired, most likely from a presymptomatic spouse who was visiting daily and diagnosed with COVID-19 before visitor restrictions and masking were implemented. Among 8370 patients with non-COVID-19-related hospitalizations discharged through June 17, 11 (0.1%) tested positive within 14 days (median time to diagnosis, 6 days; range, 1-14 days). Only 1 case was deemed likely to be hospital acquired, albeit with no known exposures. Conclusions and Relevance: In this cohort study of patients in a large academic medical center with rigorous infection control measures, nosocomial COVID-19 was rare during the height of the pandemic in the region. These findings may inform practices in other institutions and provide reassurance to patients concerned about contracting COVID-19 in hospitals.