Multiscale modeling shows how 2'-deoxy-ATP rescues ventricular function in heart failure.

2'-deoxy-ATP (dATP) improves cardiac function by increasing the rate of crossbridge cycling and Ca[Formula: see text] transient decay. However, the mechanisms of these effects and how therapeutic responses to dATP are achieved when dATP is only a small fraction of the total ATP pool remain poorly understood. Here, we used a multiscale computational modeling approach to analyze the mechanisms by which dATP improves ventricular function. We integrated atomistic simulations of prepowerstroke myosin and actomyosin association, filament-scale Markov state modeling of sarcomere mechanics, cell-scale analysis of myocyte Ca[Formula: see text] dynamics and contraction, organ-scale modeling of biventricular mechanoenergetics, and systems level modeling of circulatory dynamics. Molecular and Brownian dynamics simulations showed that dATP increases the actomyosin association rate by 1.9 fold. Markov state models predicted that dATP increases the pool of myosin heads available for crossbridge cycling, increasing steady-state force development at low dATP fractions by 1.3 fold due to mechanosensing and nearest-neighbor cooperativity. This was found to be the dominant mechanism by which small amounts of dATP can improve contractile function at myofilament to organ scales. Together with faster myocyte Ca[Formula: see text] handling, this led to improved ventricular contractility, especially in a failing heart model in which dATP increased ejection fraction by 16% and the energy efficiency of cardiac contraction by 1%. This work represents a complete multiscale model analysis of a small molecule myosin modulator from single molecule to organ system biophysics and elucidates how the molecular mechanisms of dATP may improve cardiovascular function in heart failure with reduced ejection fraction.

NetSci: A Library for High Performance Biomolecular Simulation Network Analysis Computation.

We present the NetSci program-an open-source scientific software package designed for estimating mutual information (MI) between data sets using GPU acceleration and a k-nearest-neighbor algorithm. This approach significantly enhances calculation speed, achieving improvements of several orders of magnitude over traditional CPU-based methods, with data set size limits dictated only by available hardware. To validate NetSci, we accurately compute MI for an analytically verifiable two-dimensional Gaussian distribution and replicate the generalized correlation (GC) analysis previously conducted on the B1 domain of protein G. We also apply NetSci to molecular dynamics simulations of the Sarcoendoplasmic Reticulum Calcium-ATPase (SERCA) pump, exploring the allosteric mechanisms and pathways influenced by ATP and 2'-deoxy-ATP (dATP) binding. Our analysis reveals distinct allosteric effects induced by ATP compared to dATP, with predicted information pathways from the bound nucleotide to the calcium-binding domain differing based on the nucleotide involved. NetSci proves to be a valuable tool for estimating MI and GC in various data sets and is particularly effective for analyzing intraprotein communication and information transfer.

Out of hospital cardiac arrest: experience of a bystander CPR training program in Karachi, Pakistan.

BACKGROUND: Nearly 90% of out-of-hospital cardiac arrest (OHCA) patients are witnessed, yet only 2.3% received bystander cardiopulmonary resuscitation (CPR) in Pakistan. This study aimed to determine retention of knowledge and skills of Hands-Only CPR among community participants in early recognition of OHCA and initiation of CPR in Karachi, Pakistan. METHODS: Pre and post-tests were conducted among CPR training participants from diverse non-health-related backgrounds from July 2018 to October 2019. Participants were tested for knowledge and skills of CPR before training (pre-test), immediately after training (post-test), and 6 months after training (re-test). All the participants received CPR training through video and scenario-based demonstration using manikins. Post-training CPR skills of the participants were assessed using a pre-defined performance checklist. The facilitator read out numerous case scenarios to the participants, such as drowning, poisoning, and road traffic injuries, etc., and then asked them to perform the critical steps of CPR identified in the scenario on manikins. The primary outcome was the mean difference in the knowledge score and skills of the participants related to the recognition of OHCA and initiation of CPR. RESULTS: The pre and post-tests were completed by 652 participants, whereas the retention test after 6 months was completed by 322 participants. The mean knowledge score related to the recognition of OHCA, and initiation of CPR improved significantly (p < 0.001) from pre-test [47.8/100, Standard Deviation (SD) ±13.4] to post-test (70.2/100, SD ±12.1). Mean CPR knowledge after 6 months (retention) reduced slightly from (70.2/100, ±12.1) to (66.5/100, ±10.8). CPR skill retention for various components (check for scene safety, check for response, check for breathing and correct placement of the heel of hands) deteriorated significantly (p < 0.001) from 77.9% in the post-test to 72.8% in re-test. Participants performed slightly better on achieving an adequate rate of chest compressions from 73.1% in post-test to 76.7% in re-test (p 0.27). CONCLUSION: Community members with non-health backgrounds can learn and retain CPR skills, allowing them to be effective bystander CPR providers in OHCA situations. We recommend mass population training in Pakistan for CPR to increase survival from OHCA.

Comparison of Chest Compression Quality between Transfer Sheet and Stretcher Use for Transporting out-of-Hospital Cardiac Arrest Patients in a High-Rise Building - A Randomized and Open-Label Cross-over Design.

OBJECTIVES: Stretchers are commonly used for transporting cardiac arrest patients, but their use may be limited in confined spaces, like elevators. Use of transfer sheet as an alternative has not been explored. We aimed to compare manual chest compression quality between these two methods. Methods: In this prospective, open-label, randomized cross-over manikin study, the subjects included emergency medical technicians who were assigned to 12 three-person crews. Scenarios included transport of a cardiac arrest in a high-rise building and elevator using transfer sheet (TS) and stretchers adjusted to 45° (S45) and 90° (S90). Chest compression quality was measured using a recording manikin and that before (on-scene phase) and after (transport phase) the manikin moved via transfer sheet or stretcher were compared. Results: The final analysis included 72 simulation runs. Chest compression quality did not differ among the groups in the on-scene phase. In the transport phase, the transfer sheet group provided greater mean compression depth (54.4 ± 4.2 vs 39.6 ± 7.2 mm, p < 0.01 and 54.4 ± 4.2 vs 40.6 ± 8.3 mm, p < 0.01, respectively) than stretchers of S45 and S90, and higher percentage of deep-enough compression (TS: 51.0 [23.8-74.8]% vs S45: 19.5 [5.8-29.5]%, p < 0.01) than the S45 group. Transfer sheet use showed a trend of lower percentages of full recoil (TS: 40.0 [12.8-64.5]% vs S45: 70.5 [47.0-79.8]% vs S90: 52.5 [25.3-76.0]%, p = 0.09). Chest compression fraction, compressions with correct hand position, and mean compression rates did not differ between groups in the transport phase. The TS group showed shorter time intervals of simulation start-to-first-compression (TS: 13.9 [12.4-15.1] sec vs S90: 15.9 [13.3-16.4] sec, p = 0.04) and total run time (TS: 145.7 [135.1-151.4] sec vs S90: 160.0 [151.9-175.4] sec, p < 0.01) than the S90 group. Conclusion: In this simulation, using transfer sheet outperform using stretcher for transporting cardiac arrest patients from high-rise buildings. Rescuers need to be aware of full chest recoil.

Impact of COVID-19 on acute isolation bed capacity and nursing workforce requirements: A retrospective review.

AIM: To understand the impact of COVID-19 on isolation bed capacity requirements, nursing workforce requirements and nurse:patient ratios. BACKGROUND: COVID-19 created an increased demand for isolation beds and nursing workforce globally. METHODS: This was a retrospective review of bed capacity, bed occupancy and nursing workforce data from the isolation units of a tertiary hospital in Singapore from 23 January 2020 to 31 May 2020. R v4.0.1 and Tidyverse 1.3.0 library were used for data cleaning and plotly 4.9.2.1 library for data visualization. RESULTS: In January to March 2020, isolation bed capacity was low (=<203 beds). A sharp increase in bed capacity was seen from 195 to 487 beds during 25 March to 29 April 2020, after which it plateaued. Bed occupancy remained lower than bed capacity throughout January to May 2020. After 16 April 2020, we experienced a shortage of 1.1 to 70.2 nurses in isolation wards. Due to low occupancy rates, nurse:patient ratio remained acceptable (minimum nurse:patient ratio = 0.26). CONCLUSION: COVID-19 caused drastic changes in isolation bed capacity and nursing workforce requirements. IMPLICATIONS FOR NURSING MANAGEMENT: Building a model to predict nursing workforce requirements during pandemic surges may be helpful for planning and adequate staffing.

Performance of cardiac troponins within the HEART score in predicting major adverse cardiac events at the emergency department.

BACKGROUND: This study compared the performance of a single blood draw of high-sensitivity troponin T (hsTnT), high-sensitivity troponin I (hsTnI) and conventional troponin I (cTnI) within a modified HEART score for predicting 30-day MACE at Emergency Department (ED) presentation, and established local reference norms for all three assays by determining the cut-off point which yielded the highest sensitivity and negative predictive value for acute myocardial infarction and 30-day MACE. METHODS: This single-center prospective cohort study recruited chest pain patients at the ED, whose hsTnT, hsTnI and cTnI were taken on admission. Subjects were classified into low and non-low risk group according to their modified HEART score, with MACE as the primary endpoint. Receiver-operating characteristic (ROC) curves were generated, area under the curves (AUCs) were calculated; the performance characteristics were determined. RESULTS: The performance of modified HEART scores was comparable among the three assays for 30-day MACE (84.9-87.0% sensitivity, 95.6-96.0% NPV, 95%CI) and none of these had very high AUC and specificity (AUC 0.70-0.71, 53.7-56.7% specificity, 95% CI). The modified HEART score using a single blood draw of either hsTnT (3.9ng/L), hsTnI (0.9ng/L) or cTnI (0.0ng/L) at presentation yielded a sensitivity of 100% for 30-day MACE. CONCLUSION: The modified HEART score using a single blood draw of either hsTnT, hsTnI or cTnI was equally effective in risk-stratifying chest pain patients for safe discharge. The theoretical cut-off points yielding 100% sensitivity are potentially useful (when achieved) for safely discharging low risk patients with undifferentiated chest pain in the ED.

Development of prehospital emergency care in Singapore.

This review paper describes the development of the pre-hospital system in Singapore from the pre-war days. Every country's prehospital community needs a deep understanding of how they developed over the years, factors that played a part, and the aspirations their community and government have set for this. This can guide future evolution of the services to ensure that care provided is relevant, applicable and in keeping with the community's needs. Countries with similar contextual circumstances, but at a different stage of development of their PECs, may learn from these.

Multiscale computational modeling of the effects of 2'-deoxy-ATP on cardiac muscle calcium handling.

2'-Deoxy-ATP (dATP), a naturally occurring near analog of ATP, is a well-documented myosin activator that has been shown to increase contractile force, improve pump function, and enhance lusitropy in the heart. Calcium transients in cardiomyocytes with elevated levels of dATP show faster calcium decay compared with cardiomyocytes with basal levels of dATP, but the mechanisms behind this are unknown. Here, we design and utilize a multiscale computational modeling framework to test the hypothesis that dATP acts on the sarcoendoplasmic reticulum calcium-ATPase (SERCA) pump to accelerate calcium re-uptake into the sarcoplasmic reticulum during cardiac relaxation. Gaussian accelerated molecular dynamics simulations of human cardiac SERCA2A in the E1 apo, ATP-bound and dATP-bound states showed that dATP forms more stable contacts in the nucleotide binding pocket of SERCA and leads to increased closure of cytosolic domains. These structural changes ultimately lead to changes in calcium binding, which we assessed using Brownian dynamics simulations. We found that dATP increases calcium association rate constants to SERCA and that dATP binds to apo SERCA more rapidly than ATP. Using a compartmental ordinary differential equation model of human cardiomyocyte excitation-contraction coupling, we found that these increased association rate constants contributed to the accelerated rates of calcium transient decay observed experimentally. This study provides clear mechanistic evidence of enhancements in cardiac SERCA2A pump function due to interactions with dATP.

Reducing blood sample hemolysis in the emergency department using S-Monovette® in aspiration mode.

Background: Blood sample hemolysis continues to be a significant problem in clinical practice. In vitro hemolysis rates up to 77% have been reported in literature. The use of manual aspiration techniques for blood sampling has previously been shown to reduce the burden of erythrocyte injury in the pre-analytical phase compared to the vacuum collection technique. This study compares the hemolysis rates between two blood sampling methods: 5.0 ml BD Vacutainer® SST™ (BDV) and 4.9 ml S-Monovette® serum gel tubes in aspiration mode (SMA). Methods: This was a prospective randomised controlled study conducted in an Emergency department (ED). A convenience sample of 191 adult patients, aged 18-90 years old, presenting at the ED and requiring blood samples for serum electrolyte was included in the study. Paired blood samples were obtained through an intravenous cannula from each patient with randomised order of blood draw using SMA or BDV. Patient data was obtained and hemolysis index (HI), serum lactate dehydrogenase (LDH), and serum potassium (K) levels measured. Results: The adjusted mean HI (35.2 vs 21.5 mg/dL, p < 0.001), serum K (4.38 vs 4.16 mmol/L, p < 0.001) and LDH levels (259.6 vs 228.4 U/L, p < 0.001) were significantly higher in blood samples taken using BDV compared to SMA. The frequency of severely hemolyzed (>150 mg/dL) samples was also higher in blood collected using BDV (16.2%) compared to SMA (0%). Conclusions: The burden of hemolysis in blood samples taken from IV cannulae can be effectively reduced with the use of manual aspiration using the S-Monovette® blood collection system as compared to BD-Vacutainer.

Quantitative analysis of mitochondrial ATP synthesis.

We present a computational framework for analyzing and simulating mitochondrial ATP synthesis using basic thermodynamic and kinetic principles. The framework invokes detailed descriptions of the thermodynamic driving forces associated with the processes of the electron transport chain, mitochondrial ATP synthetase, and phosphate and adenine nucleotide transporters. Assembling models of these discrete processes into an integrated model of mitochondrial ATP synthesis, we illustrate how to analyze and simulate in vitro respirometry experiments and how models identified from in vitro experimental data effectively explain cardiac respiratory control in vivo. Computer codes for these analyses are embedded as Python scripts in a Jupyter Book to facilitate easy adoption and modification of the concepts developed here. This accessible framework may also prove useful in supporting educational applications. All source codes are available on at https://beards-lab.github.io/QAMAS_book/.

Platelet inhibition to target reperfusion injury trial: Rationale and study design.

BACKGROUND: In ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI), current oral P2Y12 platelet inhibitors do not provide maximal platelet inhibition at the time of reperfusion. Furthermore, administration of cangrelor prior to reperfusion has been shown in pre-clinical studies to reduce myocardial infarct (MI) size. Therefore, we hypothesize that cangrelor administered prior to reperfusion in STEMI patients will reduce the incidence of microvascular obstruction (MVO) and limit MI size in STEMI patients treated with PPCI. METHODS: The platelet inhibition to target reperfusion injury (PITRI) trial, is a phase 2A, multi-center, double-blinded, randomized controlled trial, in which 210 STEMI patients will be randomized to receive either an intravenous (IV) bolus of cangrelor (30 µg/kg) followed by a 120-minute infusion (4 µg/kg/min) or matching saline placebo, initiated prior to reperfusion (NCT03102723). RESULTS: The study started in October 2017 and the anticipated end date would be July 2020. The primary end-point will be MI size quantified by cardiovascular magnetic resonance (CMR) on day 3 post-PPCI. Secondary endpoints will include markers of reperfusion, incidence of MVO, MI size, and adverse left ventricular remodeling at 6 months, and major adverse cardiac and cerebrovascular events. SUMMARY: The aim of the PITRI trial is to assess whether cangrelor administered prior to reperfusion would reduce acute MI size and MVO, as assessed by CMR.

Data-Driven Approach to Defining the Emergency Department Frequent Attender Using a Cohort of 10 Years.

AIMS: To identify, based on the measure of resource utilization, the number of visits per calendar year that defines the emergency department (ED) frequent attender; and examine for significant trends in patient characteristics and outcomes which may support the use of our definition. MATERIALS AND METHODS: We conducted a retrospective observational study of electronic clinical records of all ED visits over a 10-year period from January 2005 to December 2014 to an urban tertiary general hospital. We defined the ED frequent attender based on the number of ED attendances per calendar year which would yield a patient group representing more than 20% of all patient visits. Chi-square tests were conducted on each categorical factor individually to assess if they were independent of time, and the Student's t-test was used to assess continuous variables on their association with being a frequent attender. RESULTS: 1.381 million attendance records were analyzed. Patients who attended three or more times per year accounted for about 22.1% of all attendances and were defined as frequent attenders. They were associated with higher triage acuity, complex chronic illnesses, greater 30-day mortality for patients with three to six visits, and increased markers of resource utilization, such as ambulance use (15.5% vs. 11.6%), time to disposition (180 vs. 155 minutes), admissions rate (47.4% vs. 30.7%) and inpatient length of stay (6 days vs. 4 days). All p values were statistically significant (p < 0.001). CONCLUSION: We have demonstrated a data-driven approach to defining an ED frequent attender. Frequent attenders are associated with increased resource utilization, more complex illness and may be associated with greater 30-day mortality rates.

Clinical and Socio-Demographic Predictors of Home Hospice Patients Dying at Home: A Retrospective Analysis of Hospice Care Association's Database in Singapore.

CONTEXT: Hospice care can be delivered in different settings, but many patients choose to receive it at home because of familiar surroundings. Despite their preferences, not every home hospice patient manages to die at home. OBJECTIVE: To examine the independent factors associated with home hospice patient dying at home. METHODS: Retrospective analysis of Hospice Care Association's database. Hospice Care Association is the largest home hospice provider in Singapore. The study included all patients who were admitted into home hospice service from January 1, 2004 to December 31, 2013. Cox proportional hazards modeling with time as constant was used to study the relationship between independent variables and home death. RESULTS: A total of 19,721 patients were included in the study. Females (adjusted risk ratio [ARR] 1.09, 95% CI 1.04-1.15), older patients (ARR 1.01, 95% CI 1.00-1.01), shorter duration of home hospice stay (ARR 0.88, 95% CI 0.82-0.94), fewer episodes of hospitalization (ARR 0.81, 95% CI 0.75-0.86), living with caregivers (ARR 1.54, 95% CI 1.05-2.26), doctor (ARR 1.05, 95% CI 1.01-1.08) and nurse (ARR 1.06, 95% CI 1.04-1.08) visits were positive predictors of dying-at-home. Diagnosis of cancer (ARR 0.93, 95% CI 0.86-1.00) was a negative predictor of dying-at-home. CONCLUSION: Female, older age, living with a caregiver, non-cancer diagnosis, more doctor and nurse visits, shorter duration of home hospice stays, and fewer episodes of acute hospitalizations are predictive of dying-at-home for home hospice patients.

Should the Emergency Department be society's health safety net?

In the US health care system, a core safety net provider has two defining characteristics: (1) either by legal mandate or explicitly adopted mission, they maintain an "open door," offering patients services regardless of their ability to pay; and (2) a substantial portion of their patients are uninsured, on Medicaid, and/or otherwise vulnerable. The hospital Emergency Department (ED), by all accounts, falls within the definition of a core safety net provider. Yet many would argue that this is a primary health care role for which the ED was not originally intended or equipped. Should the ED be society's health-care safety net? Should it be the main provider of care for the indigent? Is this placing an unbearable strain on the ED? Should it be providing primary health-care? If not, what are the alternatives?

A randomized controlled trial comparing the hair apposition technique with tissue glue to standard suturing in scalp lacerations (HAT study).

STUDY OBJECTIVE: We evaluate a new technique of treating scalp lacerations, the hair apposition technique (HAT). After standard cleaning procedures, hair on both sides of a laceration is apposed with a single twist. This is then held with tissue adhesives. HAT was compared with standard suturing in a multicenter, randomized, prospective trial. METHODS: All linear lacerations of the scalp less than 10 cm long were included. Severely contaminated wounds, actively bleeding wounds, patients with hair strand length less than 3 cm, and hemodynamically unstable patients were excluded. Patients were randomized to receive either HAT or standard suturing, and the time to complete the wound repair was measured. All wounds were evaluated 7 days later in a nonblinded manner for satisfactory wound healing, scarring, and complications. RESULTS: There were 96 and 93 patients in the study and control groups, respectively. Wound healing trended toward being judged more satisfactory in the HAT group than standard suturing (100% versus 95.7%; P =.057; effect size 4.3%; 95% confidence interval 0.1% to 8.5%). Patients who underwent HAT had less scarring (6.3% versus 20.4%; P =.005), fewer overall complications (7.3% versus 21.5%; P =.005), significantly lower pain scores (median 2 versus 4; P <.001), and shorter procedure times (median 5 versus 15 minutes; P <.001). There was a trend toward less wound breakdown in the HAT group (0% versus 4.3%; P =.057). When patients were asked whether they were willing to have HAT performed in the future, 84% responded yes, 1% responded no, and 15% were unsure. CONCLUSION: HAT is equally acceptable and perhaps superior to standard suturing for closing suitable scalp lacerations. Advantages include fewer complications, a shorter procedure time, less pain, no need for shaving or removal of stitches, similar or superior wound healing, and high patient acceptance. HAT has become our technique of choice for suitable scalp lacerations.[Ong Eng Hock M, Ooi SBS, Saw SM, Lim SH. A randomized controlled trial comparing the hair apposition technique with tissue glue to standard suturing in scalp lacerations (HAT study).