Imaging Wisely Campaign: Initiative to Reduce Imaging for Low Back Pain Across a Large Safety Net System.

OBJECTIVES: Low back pain is a common clinical presentation that often results in expensive and unnecessary imaging that may lead to undue patient harm, including unnecessary procedures. We present an initiative in a safety net system to reduce imaging for low back pain. METHODS: This quality improvement study was conducted across 70 ambulatory clinics and 11 teaching hospitals. Three electronic health record changes, using the concept of a nudge, were introduced into orders for lumbar radiography (x-ray), lumbar CT, and lumbar MRI. The primary outcome was the number of orders per 1,000 patient-days or encounters for each imaging test in the inpatient, ambulatory, and emergency department (ED) settings. Variation across facilities was assessed, along with selected indications. RESULTS: Across all clinical environments, there were statistically significant decreases in level differences pre- and postintervention for lumbar x-ray (-52.9% for inpatient encounters, P < .001; -23.7% for ambulatory encounters, P < .001; and -17.3% for ED only encounters, P < .01). There was no decrease in ordering of lumbar CTs in the inpatient and ambulatory settings, although there was an increase in lumbar CTs in ED-only encounters. There was no difference in lumbar MRI ordering. Variation was seen across all hospitals and clinics. DISCUSSION: Our intervention successfully decreased lumbar radiography across all clinical settings, with a reduction in lumbar CTs in the inpatient and ambulatory settings. There were no changes for lumbar MRI orders.

Reducing Overuse of 3-Day Repeat Type and Screen Testing across an 11-Hospital Safety Net System.

BACKGROUND: According to the American Association of Blood Banks, a Type and Screen (T&S) is valid for up to three calendar days. Beyond a limited number of clinical indications such as a transfusion reaction, repeat T&S testing within 3 days is not warranted. Inappropriate repeat T&S testing is a costly medical waste and can lead to patient harm. OBJECTIVE: To reduce inappropriate duplicate T&S testing across a large, multihospital setting. SETTING: The largest urban safety net health system in the USA, with 11 acute care hospitals. INTERVENTIONS: Our first intervention involved adding the time elapsed since the last T&S order into the order and the process instructions that described when a T&S was indicated. The second intervention was a best practice advisory that triggered when T&S was ordered before the expiration of an active T&S. MAIN MEASURES: The primary outcome measure was the number of duplicate inpatient T&S per 1000 patient days. KEY RESULTS: Across all hospitals, the weekly average rate of duplicate T&S ordering decreased from 8.42 to 7.37 per 1000 patient days (12.5% reduction, p < 0.001) after the first intervention and to 4.32 per 1000 patient days (48.7% reduction, p < 0.001) after the second intervention. Using linear regression to compare pre-intervention to post-intervention 1, the level difference was - 2.46 (9.17 to 6.70, p < 0.001) and slope difference was 0.0001 (0.0282 to 0.0283, p = 1). For post-intervention 1 to post-intervention 2, the level difference was - 3.49 (8.06 to 4.58, p < 0.001) and slope difference was - 0.0428 (0.0283 to - 0.0145, p < 0.05). CONCLUSIONS: Our intervention successfully reduced duplicate T&S testing using a two-pronged electronic health record intervention. The success of this low effort intervention across a diverse health system provides a framework for similar interventions in various clinical settings.

Initiative to reduce unnecessary routine daily testing of complete blood counts across 11 safety net hospitals.

OBJECTIVES: National societies recommend against performing routine daily laboratory testing without a specific indication. Unnecessary testing can lead to patient harm, such as hospital-acquired anemia. The objective of this study was to reduce repeat complete blood counts (CBCs) after initial testing. METHODS: This was a quality improvement initiative implemented across 11 safety net hospitals in New York City. A best practice advisory (BPA) was implemented that asked the user to remove a CBC if the last 2 CBCs within 72 hours had normal white blood cell and platelet counts and unchanged hemoglobin levels. The outcome measure was the rate of CBCs per 1000 patient days preintervention (January 8, 2020, to December 22, 2020) to postintervention (December 23, 2020, to December 7, 2021). The process measure was the acceptance rate of the BPA, defined as the number of times the repeat CBC order was removed through the BPA divided by the total number of times the BPA triggered. RESULTS: Across 11 hospitals, repeat CBC testing decreased by 12.3% (73.05 to 64.04 per 1000 patient days, P < .001). Six of the 11 hospitals exhibited statistically significant decreases, ranging from a 10% to 48.9% decrease of repeat CBCs. The overall BPA action rate was 20.0% (24,029 of 119,944 repeat CBCs). CONCLUSIONS: This low-effort, electronic health record-based intervention can effectively reduce unnecessary laboratory testing.

Choosing Wisely and Promoting High-Value Care and Staff Safety During the COVID-19 Pandemic in a Large Safety Net System.

BACKGROUND AND OBJECTIVES: As the COVID-19 pandemic brought surges of hospitalized patients, it was important to focus on reducing overuse of tests and procedures to not only reduce potential harm to patients but also reduce unnecessary exposure to staff. The objective of this study was to create a Choosing Wisely in COVID-19 list to guide clinicians in practicing high-value care at our health system. METHODS: A Choosing Wisely in COVID-19 list was developed in October 2020 by an interdisciplinary High Value Care Council at New York City Health + Hospitals, the largest public health system in the United States. The first phase involved gathering areas of overuse from interdisciplinary staff across the system. The second phase used a modified Delphi scoring process asking participants to rate recommendations on a 5-point Likert scale based on criteria of degree of evidence, potential to prevent patient harm, and potential to prevent staff harm. RESULTS: The top 5 recommendations included avoiding tracheal intubation without trial of noninvasive ventilation (4.4); not placing routine central venous catheters (4.33); avoiding routine daily laboratory tests and batching laboratory draws (4.19); not ordering daily chest radiographs (4.17); and not using bronchodilators in the absence of reactive airway disease (4.13). CONCLUSION: We successfully developed Choosing Wisely in COVID-19 recommendations that focus on evidence and preventing patient and staff harm in a large safety net system to reduce overuse.

Neuroprotective effect of whey protein hydrolysate containing leucine-aspartate-isoleucine-glutamine-lysine on HT22 cells in hydrogen peroxide-induced oxidative stress.

This study aimed to investigate the neuroprotective effects of whey protein hydrolysate (WPH) containing the pentapeptide leucine-aspartate-isoleucine-glutamine-lysine (LDIQK). Whey protein hydrolysate (50, 100, and 200 µg/mL) demonstrated the ability to restore the viability of HT22 cells subjected to 300 µM hydrogen peroxide (H2O2)-induced oxidative stress. Furthermore, at a concentration of 200 µg/mL, it significantly reduced the increase in reactive oxygen species production and calcium ion (Ca2+) influx induced by H2O2 by 46.1% and 46.2%, respectively. Similarly, the hydrolysate significantly decreased the levels of p-tau, a hallmark of tauopathy, and BCL2 associated X (BAX), a proapoptosis factor, while increasing the protein levels of choline acetyltransferase (ChAT), an enzyme involved in acetylcholine synthesis, brain-derived neurotrophic factor (BDNF), a nerve growth factor, and B-cell lymphoma 2 (BCL2, an antiapoptotic factor. Furthermore, it increased nuclear factor erythroid 2-related factor 2 (Nrf2)-hemoxygenase-1(HO-1) signaling, which is associated with the antioxidant response, while reducing the activation of mitogen-activated protein kinase (MAPK) signaling pathway components, namely phosphor-extracellular signal-regulated kinases (p-ERK), phosphor-c-Jun N-terminal kinases (p-JNK), and p-p38. Column chromatography and tandem mass spectrometry analysis identified LDIQK as a compound with neuroprotective effects in WPH; it inhibited Ca2+ influx and regulated the BAX/BCL2 ratio. Collectively, WPH containing LDIQK demonstrated neuroprotective effects against H2O2-induced neuronal cell damage, suggesting that WPH or its active peptide, LDIQK, may serve as a potential edible agent for improving cognitive dysfunction.

Infrared Spectroscopy of Li+ Solvation in Diglyme: Ab Initio Molecular Dynamics and Experiment.

Infrared (IR) spectra of solutions of the lithium salt LiBF4 in diglyme, CH3O(CH2CH2O)2CH3, are studied via IR spectroscopy and ab initio molecular dynamics (AIMD) simulations. Experiments show that the major effects of LiBF4, compared to neat diglyme, are the appearance of a new broad band in the 250-500 cm-1 frequency region and a broadening and intensity enhancement of the diglyme band in the 900-1150 cm-1 region accompanied by a red-shift. Computational analysis indicates that hindered translational motions of Li+ in its solvation cage are mainly responsible for the new far-IR band, while the changes in the mid-IR are due to Li+-coordination-dependent B-F stretching vibrations of BF4- anions coupled with diglyme vibrations. Molecular motions in these and lower frequency regions are generally correlated, revealing the collective nature of the vibrational dynamics, which involve multiple ions/molecules. Herein, a detailed analysis of these features via AIMD simulations of the spectrum and its components, combined with analysis of the generalized normal modes of the solution components, is presented. Other minor spectral changes as well as diglyme conformational changes induced by the lithium salt are also discussed.

Reducing low-value ED coags across 11 hospitals in a safety net setting.

BACKGROUND: Prothrombin/international normalized ratio and activated partial thromboplastin time (PT/INR and aPTT) are frequently ordered in emergency departments (EDs), but rarely affect management. They offer limited utility outside of select indications. Several quality improvement initiatives have shown reduction in ED use of PT/INR and aPTT using multifaceted interventions in well-resourced settings. Successful reduction of these low-value tests has not yet been shown using a single intervention across a large hospital system in a safety net setting. This study aims to determine if an intervention of two BPAs is associated with a reduction in PT/INR and aPTT usage across a large safety net system. METHODS: This initiative was set at a large safety net system in the United States with 11 acute care hospitals. Two Best Practice Advisories (BPAs) discouraging inappropriate PT/INR and aPTT use were implemented from March 16, 2022-August 30, 2022. Order rate per 100 ED patients during the pre-intervention period was compared to the post-intervention period on both the system and individual hospital level. Complete blood count (CBC) testing served as a control, and packed red blood cell transfusions served as a balancing measure. An interrupted time series regression analysis was performed to capture immediate and temporal changes in ordering for all tests in the pre and post-intervention periods. RESULTS: PT/INR tests exhibited an absolute decline of 4.11 tests per 100 ED encounters (95% confidence interval -5.17 to -3.05; relative reduction of 18.9%). aPTT tests exhibited absolute decline of 4.03 tests per 100 ED encounters (95% CI -5.10 to -2.97; relative reduction of 19.8%). The control measure, CBC, did not significantly change (-0.43, 95% CI -2.83 to 1.96). Individual hospitals showed variable response, with absolute reductions from 2.02 to 9.6 tests per 100 ED encounters for PT/INR (relative reduction 12.1%-30.5%) and 2.07 to 10.04 for aPTT (relative reduction 12.1%-31.4%). Regression analysis showed that the intervention caused an immediate 25.7% decline in PT/INR and 24.7% decline in aPTT tests compared to the control measure. The slope differences (rate of order increase pre vs post intervention) did not significantly decline compared to the control. CONCLUSIONS: This BPA intervention reduced PT/INR and aPTT use across 11 EDs in a large, urban, safety net system. Further study is needed in implementation to other non-safety net settings.

Choosing Wisely and reducing the simultaneous ordering of erythrocyte sedimentation rate and C-reactive protein testing in a large safety net system.

OBJECTIVES: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are commonly used inflammatory markers. C-reactive protein is more sensitive and specific for monitoring acute inflammation. However, it is commonly co-ordered with ESR despite recommendations against this. Our objective was to reduce unnecessary ESR orders and ESR/CRP co-ordering rates across a large safety net health system. METHODS: This was a quality improvement project that used a quasi-experimental pre- and postintervention interrupted time-series regression analysis. Patients with a positive COVID-19 test were excluded. We designed a nonintrusive, normative nudge within the ESR order that recommended against co-ordering ESR and CRP. In addition, a best practice advisory triggered when ESR and CRP were simultaneously ordered. The outcome measures were ESR order rates per 1000 patient days in the inpatient setting and per 1000 patient encounters in the outpatient setting, as well as ESR/CRP co-ordering rates. RESULTS: Inpatient ESR orders decreased from 12.02 preintervention to 5.61 per 1000 patient days (-53.3%, P < .001). Outpatient ESR orders decreased from 6.09 to 4.07 per 1000 patient encounters (-33.2%, P < .001). Relative co-ordering rates decreased by 50%. CONCLUSIONS: This electronic health record initiative successfully reduced ESR testing across 11 hospitals and 70 ambulatory centers in a safety net setting.

Safety and efficacy of trastuzumab biosimilar plus irinotecan or gemcitabine in patients with previously treated HER2 (ERBB2)-positive non-breast/non-gastric solid tumors: a phase II basket trial with circulating tumor DNA analysis.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) (ERBB2)-directed agents are standard treatments for patients with HER2-positive breast and gastric cancer. Herein, we report the results of an open-label, single-center, phase II basket trial to investigate the efficacy and safety of trastuzumab biosimilar (Samfenet®) plus treatment of physician's choice for patients with previously treated HER2-positive advanced solid tumors, along with biomarker analysis employing circulating tumor DNA (ctDNA) sequencing. METHODS: Patients with HER2-positive unresectable or metastatic non-breast, non-gastric solid tumors who failed at least one prior treatment were included in this study conducted at Asan Medical Center, Seoul, Korea. Patients received trastuzumab combined with irinotecan or gemcitabine at the treating physicians' discretion. The primary endpoint was the objective response rate as per RECIST version 1.1. Plasma samples were collected at baseline and at the time of disease progression for ctDNA analysis. RESULTS: Twenty-three patients were screened from 31 December 2019 to 17 September 2021, and 20 were enrolled in this study. Their median age was 64 years (30-84 years), and 13 patients (65.0%) were male. The most common primary tumor was hepatobiliary cancer (seven patients, 35.0%), followed by colorectal cancer (six patients, 30.0%). Among 18 patients with an available response evaluation, the objective response rate was 11.1% (95% confidence interval 3.1% to 32.8%). ERBB2 amplification was detected from ctDNA analysis of baseline plasma samples in 85% of patients (n = 17), and the ERBB2 copy number from ctDNA analysis showed a significant correlation with the results from tissue sequencing. Among 16 patients with post-progression ctDNA analysis, 7 (43.8%) developed new alterations. None of the patients discontinued the study due to adverse events. CONCLUSIONS: Trastuzumab plus irinotecan or gemcitabine was safe and feasible for patients with previously treated HER2-positive advanced solid tumors with modest efficacy outcomes, and ctDNA analysis was useful for detecting HER2 amplification.

Reducing daily dosing in opioid prescriptions in 11 safety net emergency departments.

BACKGROUND: The United States continues to face a significant issue with opioid misuse, overprescribing, dependency, and overdose. Electronic health record (EHR) interventions have shown to be an effective tool to modify opioid prescribing behaviors. This quality improvement project describes an EHR intervention to reduce daily dosing in opioid prescriptions in 11 emergency departments (ED) across the largest safety net health system in the US. MEASURES: The primary outcome measure was the rates of oxycodone-acetaminophen 5-325 mg prescriptions exceeding 50 morphine milligram equivalents per day (MMED) pre- vs. post-intervention; and stratified by individual hospitals and provider type. INTERVENTION: The defaults for dose and frequency were uniformly changed to 'every 6 hours as needed' and '1 tablet', respectively, across 11 EDs. OUTCOMES: The percentage of prescriptions greater than or equal to 50 MMED decreased from 46.0% (1624 of 3530 prescriptions) to 1.6% (52 of 3165 prescriptions) (96.4% relative reduction; p < 0.001). All 11 hospitals had a significant reduction in prescriptions exceeding 50 MMED. Nurse practitioners had the highest relative reduction of prescriptions exceeding 50 MMED at 100% (p < 0.001), and the attendings/fellows had the lowest relative reduction at 95.6% (p < 0.001). CONCLUSIONS/LESSONS LEARNED: Default nudges are a simple yet powerful intervention that can strongly influence opioid prescribing patterns.

Spectroscopic and Chemical Properties of Ionic Liquids: Computational Study.

A brief account is given of highlights of our computational efforts - often in collaboration with experimental groups - to understand spectroscopic and chemical properties of ionic liquids (ILs). Molecular dynamics, including their inhomogeneous character, responsible for key spectral features observed in dielectric absorption, infra-red (IR) and fluorescence correlation spectroscopy (FCS) measurements are elucidated. Mechanisms of chemical processes involving imidazolium-based ILs are illustrated for CO2 capture and related reactions, transesterification of cellulose, and Au nanocluster-catalyzed Suzuki cross-coupling reaction with attention paid to differing roles of IL ions. A comparison with experiments is also made.

Reducing duplicate genetic testing in inpatient and outpatient settings across a large safety-net system.

OBJECTIVES: To develop a system-wide electronic health record (EHR) intervention at a large safety-net hospital system to reduce wasteful duplicate genetic testing. METHODS: This project was initiated at a large urban public health care system. An EHR alert was designed to be triggered when a clinician attempted to order any of 16 specified genetic tests for which a previous result existed within the EHR system. Measurements included the proportion of completed genetic tests that were duplicates and alerts per 1,000 tests. Data were stratified by clinician type, specialty, and inpatient vs ambulatory setting. RESULTS: Across all settings, the rate of duplicate genetic testing decreased from 2.35% (1,050 of 44,592 tests) to 0.09% (21 of 22,323 tests) (96% relative reduction, P < .001). The alert rate per 1,000 tests was 277 for inpatient orders and 64 for ambulatory orders. Among clinician types, residents had the highest alert rate per 1,000 tests at 166 and midwives the lowest at 51 (P < .01). Among clinician specialties, internal medicine had the highest alert rate per 1,000 tests at 245 and obstetrics and gynecology the lowest at 56 (P < .01). CONCLUSIONS: The EHR intervention successfully reduced duplicate genetic testing by 96% across a large safety-net setting.

Reducing Inappropriate Simultaneous Ordering of Heparin Antibody and Serotonin Release Assays.

INTRODUCTION: A 4T score with intermediate or high probability of heparin-induced thrombocytopenia prompts ordering of anti-platelet 4 heparin complex. If positive, a serotonin release assay (SRA) is recommended to confirm diagnosis. Despite these recommendations, overtesting of both anti-platelet 4 and SRA is highly prevalent. METHODS: This was a quality improvement initiative using two forms of clinical decision support across 11 acute care hospitals. First, a 4T calculator was incorporated into anti-platelet 4 orders. Second, a Best Practice Advisory fired when anti-platelet 4 and SRA were ordered simultaneously, prompting the provider to remove the SRA order. Data were analyzed by a quasi-experimental interrupted time series linear regression comparing weekly average laboratory tests per 1,000 patient-days pre- and postintervention. RESULTS: Average ordering frequency of anti-platelet 4 changed from 0.508 to 0.510 per 1,000 patient-days (0.5%, p = 0.42) without significant slope or level differences. Average ordering frequency of SRA decreased from 0.430 to 0.289 per 1,000 patient-days (32.8%, p < 0.001) with a significant level difference of -0.128 orders per 1,000 patient-days (-31.2%, p < 0.05). CONCLUSION: A simultaneous Best Practice Advisory was effective in reducing SRA orders, but not anti-platelet 4 orders.

Reducing 25-Hydroxyvitamin D Testing in a Large, Urban Safety Net System.

BACKGROUND: 25-Hydroxyvitamin D testing is increasing despite national guidelines and Choosing Wisely recommendations against routine screening. Overuse can lead to misdiagnosis and unnecessary downstream testing and treatment. Repeat testing within 3 months is a unique area of overuse. OBJECTIVE: To reduce 25-hydroxyvitamin D testing in a large safety net system comprising 11 hospitals and 70 ambulatory centers. DESIGN: This was a quality improvement initiative with a quasi-experimental interrupted time series design with segmented regression. PARTICIPANTS: All patients in the inpatient and outpatient settings with at least one order for 25-hydroxyvitamin D were included in the analysis. INTERVENTIONS: An electronic health record clinical decision support tool was designed for inpatient and outpatient orders and involved two components: a mandatory prompt requiring appropriate indications and a best practice advisory (BPA) focused on repeat testing within 3 months. MAIN MEASURES: The pre-intervention period (6/17/2020-6/13/2021) was compared to the post-intervention period (6/14/2021-8/28/2022) for total 25-hydroxyvitamin D testing, as well as 3-month repeat testing. Hospital and clinic variation in testing was assessed. Additionally, best practice advisory action rates were analyzed, separated by clinician type and specialty. KEY RESULTS: There were 44% and 46% reductions in inpatient and outpatient orders, respectively (p < 0.001). Inpatient and outpatient 3-month repeat testing decreased by 61% and 48%, respectively (p < 0.001). The best practice advisory true accept rate was 13%. CONCLUSION: This initiative successfully reduced 25-hydroxyvitamin D testing through the use of mandatory appropriate indications and a best practice advisory focusing on a unique area of overuse: the repeat testing within a 3-month interval. There was wide variation among hospitals and clinics and variation among clinician types and specialties regarding actions to the best practice advisory.

Initiative to reduce inappropriate venous thromboembolism prophylaxis in an 11-hospital safety net system: An electronic health records-based approach.

BACKGROUND: While pharmacologic prophylaxis has benefits for venous thromboembolism (VTE) prevention in high-risk patients, unnecessary use carries potential harm, including bleeding, heparin-induced thrombocytopenia, and patient discomfort, and should be avoided in low-risk patients. While many quality improvement initiatives aim to reduce underuse, successful models on reducing overuse are sparse in the literature. OBJECTIVE: We aimed to create a quality improvement initiative to reduce overuse of pharmacologic VTE prophylaxis. DESIGNS, SETTINGS AND PARTICIPANTS: A quality improvement initiative was implemented across 11 safety net hospitals in New York City. INTERVENTION: The first electronic health record (EHR) intervention consisted of a VTE order panel that facilitated risk assessment and recommended VTE prophylaxis for high-risk patients only. The second EHR intervention used a best practice advisory that alerted clinicians when prophylaxis was ordered for a patient previously deemed "low risk." Prescribing rates were compared through a three-segment interrupted time series linear regression design. RESULTS: Compared to the preintervention period, the first intervention did not change the rate of total pharmacologic prophylaxis immediately after implementation (1.7% relative change, p = .38) or over time (slope difference of 0.20 orders per 1000 patient days, p = .08). Compared to the first intervention period, the second intervention led to an immediate 4.5% reduction in total pharmacologic prophylaxis (p = .04) but increased thereafter (slope difference of 0.24, p = .03) such that weekly rates at the end of the study were similar to rates prior to the second intervention.

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome.

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2-41.2) vs. 32.1 (26.8-38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated. In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.