Comparison of admittance and cardiac magnetic resonance generated pressure-volume loops in a porcine model.

Objective. Pressure-volume loop analysis, traditionally performed by invasive pressure and volume measurements, is the optimal method for assessing ventricular function, while cardiac magnetic resonance (CMR) imaging is the gold standard for ventricular volume estimation. The aim of this study was to investigate the agreement between the assessment of end-systolic elastance (Ees) assessed with combined CMR and simultaneous pressure catheter measurements compared with admittance catheters in a porcine model.Approach. Seven healthy pigs underwent admittance-based pressure-volume loop evaluation followed by a second assessment with CMR during simultaneous pressure measurements.Main results. Admittance overestimated end-diastolic volume for both the left ventricle (LV) and the right ventricle (RV) compared with CMR. Further, there was an underestimation of RV end-systolic volume with admittance. For the RV, however, Ees was systematically higher when assessed with CMR plus simultaneous pressure measurements compared with admittance whereas there was no systematic difference in Ees but large differences between admittance and CMR-based methods for the LV.Significance. LV and RV Ees can be obtained from both admittance and CMR based techniques. There were discrepancies in volume estimates between admittance and CMR based methods, especially for the RV. RV Ees was higher when estimated by CMR with simultaneous pressure measurements compared with admittance.

Effect of opioid-free anesthesia on post-operative period in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a propensity score matched study.

BACKGROUND: Postoperative pain after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is important. It appears essential to reduce postoperative pain and morphine consumption. METHODS: Retrospective study in a university hospital comparing patient benefiting from CRS-HIPEC under opioid-free anesthesia (OFA; dexmedetomidine) to those anesthetized with opioid anesthesia (OA; remifentanil) using a propensity score matching method. The main objective was the impact of OFA on postoperative morphine consumption in the first 24 h after surgery. RESULTS: 102 patients were included, matching on the propensity score allowed selecting 34 unique pairs analyzed. Morphine consumption was lower in the OFA group than in the OA group (3.0 [0.00-11.0] mg/24 h vs. 13.0 [2.5-25.0] mg/24 h; p = 0.02). In multivariable analysis, OFA was associated with a reduction of 7.2 [0.5-13.9] mg of postoperative morphine (p = 0.04). The rate of renal failure with a KDIGO-score > 1 was lower in the OFA group than in the OA group (12% vs. 38%; p = 0.01). There was no difference between groups concerning length of surgery/anesthesia, norepinephrine infusion, volume of fluid therapy, post-operative complications, rehospitalization or ICU readmission within 90 days, mortality, and postoperative rehabilitation. CONCLUSION: Our results suggest that OFA for CRS-HIPEC patients appears safe and is associated with less postoperative morphine use and acute kidney injury.

Increasing Levels of Positive End-expiratory Pressure Cause Stepwise Biventricular Stroke Work Reduction in a Porcine Model.

BACKGROUND: Positive end-expiratory pressure (PEEP) is commonly applied to avoid atelectasis and improve oxygenation in patients during general anesthesia but affects cardiac pressures, volumes, and loading conditions through cardiorespiratory interactions. PEEP may therefore alter stroke work, which is the area enclosed by the pressure-volume loop and corresponds to the external work performed by the ventricles to eject blood. The low-pressure right ventricle may be even more susceptible to PEEP than the left ventricle. The authors hypothesized that increasing levels of PEEP would reduce stroke work in both ventricles. METHODS: This was a prospective, observational, experimental study. Six healthy female pigs of approximately 60 kg were used. PEEP was stepwise increased from 0 to 5, 7, 9, 11, 13, 15, 17, and 20 cm H2O to cover the clinical spectrum of PEEP. Simultaneous, biventricular invasive pressure-volume loops, invasive blood pressures, and ventilator data were recorded. RESULTS: Increasing PEEP resulted in stepwise reductions in left (5,740 ± 973 vs. 2,303 ± 1,154 mmHg · ml; P < 0.001) and right (2,064 ± 769 vs. 468 ± 133 mmHg · ml; P < 0.001) ventricular stroke work. The relative stroke work reduction was similar between the two ventricles. Left ventricular ejection fraction, afterload, and coupling were preserved. On the contrary, PEEP increased right ventricular afterload and caused right ventriculo-arterial uncoupling (0.74 ± 0.30 vs. 0.19 ± 0.13; P = 0.01) with right ventricular ejection fraction reduction (64 ± 8% vs. 37 ± 7%, P < 0.001). CONCLUSIONS: A stepwise increase in PEEP caused stepwise reduction in biventricular stroke work. However, there are important interventricular differences in response to increased PEEP levels. PEEP increased right ventricular afterload leading to uncoupling and right ventricular ejection fraction decline. These findings may support clinical decision-making to further optimize PEEP as a means to balance between improving lung ventilation and preserving right ventricular function.

Comparison of Two Dexmedetomidine Administration Strategies on the Incidence of Postoperative Respiratory Complications: A Retrospective, Inverse Probability of Treatment Weighted Study.

Randomized controlled trials have shown a higher risk of postoperative hypoxemia and delayed extubation with opioid-free anesthesia (OFA), compared with opioid anesthesia. The practice of OFA is not standardized. The objective of this study is to investigate the association between the dexmedetomidine administration protocol used and the occurrence of postoperative respiratory complications. This work is a retrospective, propensity score-adjusted study (inverse probability of treatment weighting) conducted between January 2019 and September 2021 in a French tertiary care university hospital, including 180 adult patients undergoing major digestive surgery. Comparison of 2 anesthesia protocols: with a continuous intravenous maintenance dose of dexmedetomidine following a bolus (group B+M, n = 105) or with a bolus dose alone (group B, n = 75). The main outcome measure was a composite respiratory end point within 24 hours of surgery. There was no significant difference in the incidence of overall respiratory complications, as assessed by the primary end point. Nevertheless, there were more patients with postoperative hypercapnia in group B+M than in group B (16% vs 2.5%, P = .004). Patients in group B+M were extubated later than patients in group B (group B+M, median 40 minutes, IQR 20-74 minutes; group B, median 20 minutes, IQR 10-50 minutes; P = .004). Our study showed negative results for the primary end point. However, data on the increased risk of postoperative hypercapnia in patients receiving a maintenance dose of dexmedetomidine are new. Other prospective randomized studies with greater power are necessary to confirm these data and to make OFA safer, by reducing the prescribed doses of dexmedetomidine.

Automated detection of cardiac rest period for trigger delay calculation for image-based navigator coronary magnetic resonance angiography.

BACKGROUND: Coronary magnetic resonance angiography (coronary MRA) is increasingly being considered as a clinically viable method to investigate coronary artery disease (CAD). Accurate determination of the trigger delay to place the acquisition window within the quiescent part of the cardiac cycle is critical for coronary MRA in order to reduce cardiac motion. This is currently reliant on operator-led decision making, which can negatively affect consistency of scan acquisition. Recently developed deep learning (DL) derived software may overcome these issues by automation of cardiac rest period detection. METHODS: Thirty individuals (female, n = 10) were investigated using a 0.9 mm isotropic image-navigator (iNAV)-based motion-corrected coronary MRA sequence. Each individual was scanned three times utilising different strategies for determination of the optimal trigger delay: (1) the DL software, (2) an experienced operator decision, and (3) a previously utilised formula for determining the trigger delay. Methodologies were compared using custom-made analysis software to assess visible coronary vessel length and coronary vessel sharpness for the entire vessel length and the first 4 cm of each vessel. RESULTS: There was no difference in image quality between any of the methodologies for determination of the optimal trigger delay, as assessed by visible coronary vessel length, coronary vessel sharpness for each entire vessel and vessel sharpness for the first 4 cm of the left mainstem, left anterior descending or right coronary arteries. However, vessel length of the left circumflex was slightly greater using the formula method. The time taken to calculate the trigger delay was significantly lower for the DL-method as compared to the operator-led approach (106 ± 38.0 s vs 168 ± 39.2 s, p < 0.01, 95% CI of difference 25.5-98.1 s). CONCLUSIONS: Deep learning-derived automated software can effectively and efficiently determine the optimal trigger delay for acquisition of coronary MRA and thus may simplify workflow and improve reproducibility.

Clinical presentation and cardiac imaging findings in patient cases of perimyocarditis and pericarditis with a temporal association to SARS-CoV-2 vaccination.

Aims: We aimed to investigate and present cases of perimyocarditis and pericarditis verified by cardiovascular resonance (CMR) imaging in patients with a strong temporal association to SARS-CoV-2 vaccination. We sought to describe the clinical presentation including coronary artery angiography, CMR, transthoracic echocardiography, blood samples, electrocardiography, and symptoms. Methods: We included 10 patients admitted with chest pain shortly after vaccination for SARS-CoV-2, who were diagnosed with pericarditis or perimyocarditis by CMR. We reviewed the CMR, echocardiography, electrocardiography, blood samples, coronary artery angiography, vital signs and medical history. The updated Lake Louise Criteria were used to determine the diagnosis by CMR. Results: Eight patients had perimyocarditis and two patients had pericarditis. The mean age was 22 ± 5 years (range 16 to 31 years), 90% were male. The median time from vaccination to hospital admission was 4 days (range 2 to 28 days). Admissions were seen after vaccination with three different SARS-CoV-2 vaccine manufacturers. Nine Patients had ST-elevation on the initial electrocardiography. Peak troponins varied from 357 to 23,547 ng/l, with a median of 4,304 ng/l. Two patients had an LVEF <50% on echocardiography and four patients had left ventricular global longitudinal strain values <18%. CMR revealed preserved left ventricular ejection fraction (LVEF), although one patient had decreased LVEF on CMR. The T1 and T2 mapping values were increased in all patients. Of the 8 patients with perimyocarditis, all patients had signs of myocardial injury in the lateral segments of the left ventricle. Conclusions: This case series of 10 patients supports the emerging evidence of an association between vaccination for SARS-CoV-2 and perimyocarditis and pericarditis, especially in young males. The temporal association was seen after vaccines from three different manufacturers. Imaging data from echocardiography and CMR displayed normal to mildly impaired cardiac function, usually with a mild disease course.

Cardiac Performance and Cardiopulmonary Fitness After Infection With SARS-CoV-2.

Aims: Persistent cardiac symptoms are an increasingly reported phenomenon following COVID-19. However, the underlying cause of cardiac symptoms is unknown. This study aimed to identify the underlying causes, if any, of these symptoms 1 year following acute COVID-19 infection. Methods and Results: 22 individuals with persistent cardiac symptoms were prospectively investigated using echocardiography, cardiovascular magnetic resonance (CMR), 6-min walking test, cardio-pulmonary exercise testing and electrocardiography. A median of 382 days (IQR 368, 442) passed between diagnosis of COVID-19 and investigation. As a cohort their echocardiography, CMR, 6-min walking test and exercise testing results were within the normal ranges. There were no differences in left ventricular ejection fraction (61.45 ± 6.59 %), global longitudinal strain (19.80 ± 3.12 %) or tricuspid annular plane systolic excursion (24.96 ± 5.55 mm) as measured by echocardiography compared to a healthy control group. VO2 max (2045.00 ± 658.40 ml/min), % expected VO2 max (114.80 ± 23.08 %) and 6-minute distance walked (608.90 ± 54.51 m) exceeded that expected for the patient cohort, whilst Troponin I (5.59 ± 6.59 ng/l) and Nt-proBNP (88.18 ± 54.27 ng/l) were normal. Conclusion: Among a cohort of 22 patients with self-reported persistent cardiac symptoms, we identified no underlying cardiac disease or reduced cardiopulmonary fitness 1 year following COVID-19.

Effect of remote ischaemic conditioning on left ventricular function in ST-segment elevation myocardial infarction patients: The CONDI-2 echocardiographic sub-study.

Background: Remote ischaemic conditioning (RIC) applied to the arm by inflation and deflation of a pneumatic cuff has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (PPCI). However, the effect of RIC on left ventricular ejection fraction (LVEF) following infarct healing remains unknown. Objective: To investigate whether RIC applied in the ambulance before PPCI can improve left ventricular (LV) function in STEMI patients 3 months following infarction. Methods: Echocardiography was performed in a total of 694 patients from the CONDI-2 study a median of 112 days (IQR 63) after the initial admission. LVEF and LV end-diastolic and end-systolic volumes were calculated using the modified Simpsons biplane method of disks. LV global longitudinal strain (GLS) was estimated using 2-dimensional cine-loops with a frame rate > 55 frames/second, measured in the three standard apical views. Results: There was no difference in the measured echocardiographic parameters in the RIC group as compared to the control group, including LV EF, LV GLS, tricuspid annular plane systolic excursion or left ventricular volumes. In the control group, 32% had an ejection fraction < 50% compared to 37% in the RIC group (p = 0.129). Conclusion: In this largest to date randomized imaging study of RIC, RIC as an adjunct to PPCI was not associated with a change in echocardiographic measures of cardiac function compared to standard PPCI alone.

Veno-occlusive unloading of the heart reduces infarct size in experimental ischemia-reperfusion.

Mechanical unloading of the left ventricle reduces infarct size after acute myocardial infarction by reducing cardiac work. Left ventricular veno-occlusive unloading reduces cardiac work and may reduce ischemia and reperfusion injury. In a porcine model of myocardial ischemia-reperfusion injury we randomized 18 pigs to either control or veno-occlusive unloading using a balloon engaged from the femoral vein into the inferior caval vein and inflated at onset of ischemia. Evans blue and 2,3,5-triphenyltetrazolium chloride were used to determine the myocardial area at risk and infarct size, respectively. Pressure-volume loops were recorded to calculate cardiac work, left ventricular (LV) volumes and ejection fraction. Veno-occlusive unloading reduced infarct size compared with controls (Unloading 13.9 ± 8.2% versus Control 22.4 ± 6.6%; p = 0.04). Unloading increased myocardial salvage (54.8 ± 23.4% vs 28.5 ± 14.0%; p = 0.02), while the area at risk was similar (28.4 ± 6.7% vs 27.4 ± 5.8%; p = 0.74). LV ejection fraction was preserved in the unloaded group, while the control group showed a reduced LV ejection fraction. Veno-occlusive unloading reduced myocardial infarct size and preserved LV ejection fraction in an experimental acute ischemia-reperfusion model. This proof-of-concept study demonstrated the potential of veno-occlusive unloading as an adjunctive cardioprotective therapy in patients undergoing revascularization for acute myocardial infarction.

Total Pelvic Exenteration, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy for Rectal Cancer with Associate Peritoneal Metastases: Surgical Strategies to Optimize Safety.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a curative treatment option for patients with peritoneal carcinomatosis. Total pelvic exenteration (TPE) is an established treatment option for locally advanced pelvic malignancy. These two procedures have high mortality and morbidity, and therefore, their combination is not currently recommended. Herein, we reported our experience on TPE associated with CRS/HIPEC with a critical analysis for rectal cancer with associate peritoneal metastases. METHODS: From March 2006 to August 2020, 319 patients underwent a CRS/HIPEC in our hospital. Among them, 16 (12 men and four women) underwent an associated TPE. The primary endpoints were perioperative morbidity and mortality. RESULTS: There was locally recurrent rectal cancer in nine cases, six locally advanced primary rectal cancer, and a recurrent appendiceal adenocarcinoma. The median Peritoneal Cancer Index (PCI) was 8. (4-16). Mean duration of the surgical procedure was 596 min (420-840). Complete cytoreduction (CC0) was achieved in all patients, while clear resection (R0) margins on the resected pelvic organs were achieved in 81.2% of cases. The median hospital stay was 46 days (26-129), and nine patients (56.2%) experienced severe complications (grade III to V) that led to death in two cases (12.5%). The total reoperation rate for patients was 6/16 (37.5%) and 3/16 (18.75%) with percutaneous radiological-guided drainage. CONCLUSIONS: In summary, TPE/extended TPE (ETPE) associated with CRS/HIPEC may be a reasonable procedure in selected patients at expert centers. Pelvic involvement should not be considered a definitive contraindication for CRS/HIPEC in patients with resectable peritoneal surface diseases if a R0 resection could be achieved on all sites. However, the morbidity and the mortality are high with this combination of treatment, and further research is needed to assess the oncologic benefit and quality of life before such a radical approach can be recommended.

Left Ventricular Assist Device Inflow Cannula Insertion Depth Influences Thrombosis Risk.

Left ventricular assist device (LVAD) use has continued to grow. Despite recent advances in technology, LVAD patients continue to suffer from devastating complications, including stroke and device thrombosis. Among several variables affecting thrombogenicity, we hypothesize that insertion depth of the inflow cannula into the left ventricle (LV) influences hemodynamics and thrombosis risk. Blood flow patterns were studied in a patient-derived computational model of the LV, mitral valve (MV), and LVAD inflow cannula using unsteady computational fluid dynamics (CFD). Hundreds of thousands of platelets were tracked individually, for two inflow cannula insertion depth configurations (12 mm-reduced and 27 mm-conventional) using platelet-level (Lagrangian) metrics to quantify thrombogenicity. Particularly in patients with small LV dimensions, the deeper inflow cannula insertion resulted in much higher platelet shear stress histories (SH), consistent with markedly abnormal intraventricular hemodynamics. A larger proportion of platelets in this deeper insertion configuration was found to linger in the domain for long residence times (RT) and also accumulated much higher SH. The reduced inflow depth configuration promoted LV washout and reduced platelet SH. The increase of both SH and RT in the LV demonstrates the impact of inflow cannula depth on platelet activation and increased stroke risk in these patients. Inflow cannula depth of insertion should be considered as an opportunity to optimize surgical planning of LVAD therapy.

Accuracy of Doppler blood pressure measurement in continuous-flow left ventricular assist device patients.

AIMS: Accurate blood pressure (BP) measurement in continuous-flow ventricular assist device (CF-VAD) patients is imperative to reduce stroke risk. This study assesses the accuracy of the Doppler opening pressure method compared with the gold standard arterial line method in CF-VAD patients. METHODS AND RESULTS: In a longitudinal cohort of HeartMate II and HVAD patients, arterial line BP and simultaneously measured Doppler opening pressure were obtained. Overall correlation, agreement between Doppler opening pressure and arterial line mean vs. systolic pressure, and the effect of arterial pulsatility on the accuracy of Doppler opening pressure were analysed. A total of 1933 pairs of Doppler opening pressure and arterial line pressure readings within 1 min of each other were identified in 154 patients (20% women, mean age 55 ± 15, 50% HeartMate II and 50% HVAD). Doppler opening pressure had good correlation with invasive mean arterial pressure (r = 0.742, P < 0.0001) and more closely approximated mean than systolic BP (mean error 2.4 vs. -8.4 mmHg). Arterial pulsatility did not have a clinically significant effect on the accuracy of the Doppler opening pressure method. CONCLUSIONS: Doppler opening pressure should be the standard non-invasive method of BP measurement in CF-VAD patients.

Evolution of stress in anaesthesia registrars with repeated simulated courses: An observational study.

BACKGROUND AND OBJECTIVE: High-fidelity medical simulation is a source of stress for participants. The aim of this study was to assess if repeated simulated courses decrease perceived stress and/or physiological stress level and increase performance in anaesthesiology registrars. METHOD: Fourteen anaesthesiology specialty registrars participated individually in three successive sessions of crisis simulation in the operating room. Participants' perceived stress levels were measured by self-assessment (simple numerical scale from 0 to 10 [0=no stress, 10=maximum stress]) and physiological stress was estimated via the maximal heart rate measured by a Holter system). Technical and non-technical performances were also assessed. Data are expressed as medians with interquartile ranges and extremes (median (IQR [Min-Max])). RESULTS: Between the first and third session, simulation repetition was associated with a decrease in perceived stress (9 (8-10 [5-10]) versus 7 (5-8 [2-9]) from session 1 to session 3 respectively, P=0.02), whereas physiological stress assessed by the maximum heart rate remained unchanged (130 beats per minute (116-141 [85-170]) and 123 beats per minute (115-136 [88-166]) between sessions 1 and 3 respectively). There was also a significant inverse correlation between perceived stress levels experienced by registrars during the session and non-technical performance (P=0.008). CONCLUSION: We observed a reduction in perceived stress levels experienced by registrars while physiological stress was unchanged with repeating simulation sessions combining simulated practice and debriefing. Learning through simulation could improve perceived stress management in critical situations.

Does Intraoperative Systematic Bacterial Sampling During Complete Cytoreductive Surgery (CRS) with Hyperthermic Intraoperative Peritoneal Chemotherapy (HIPEC) Influence Postoperative Treatment? A New Predictive Factor for Postoperative Abdominal Infectious Complications.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is an emerging curative treatment option for patients with peritoneal carcinomatosis. It has a long-term survival benefit but is associated with high rates of morbidity, ranging from 12 % to 65 %, mainly due to infectious complications. We sought to evaluate the clinical relevance of routine intraoperative bacteriological sampling following CRS/HIPEC. STUDY DESIGN: Between November 2010 and December 2014, every patients receiving CRS/HIPEC were included. Three samples were routinely collected from standardized locations for intraperitoneal rinsing liquid bacteriological analysis (RLBA) after completion of HIPEC. The clinical and surgical features, bacteriological results, and short-term outcomes were retrospectively reviewed. RESULTS: The overall mortality and morbidity rates were 5 and 45 %, respectively. Among the 75 included patients, 40 % (n = 30) had at least one positive bacterial culture. Risk factors for a positive culture were colorectal resection (adjusted hazard ratio [HR] = 3.072, 95 % CI 1.843-8.004; p = 0.009) and blood loss >1000 mL (HR = 4.272, 95 % CI 1.080-18.141; p = 0.031). Among 26 (35 %) patients with abdominal infectious complications, 13 (17 %) experienced isolated complications. A positive RLBA result was independently associated with abdominal infectious complications (HR = 5.108, 95 % CI 1.220-16.336; p = 0.024) and isolated abdominal infectious complications (HR = 4.199, 95 % CI 1.064-15.961; p = 0.04). CONCLUSIONS: Forty percent of the RLBA samples obtained following CRS/HIPEC tested positive for bacteria. Bacterial sampling of rinsing liquid should be systematically performed. An aggressive and immediate antibiotic strategy needs to be evaluated.

Using a Concept Inventory to Assess the Reasoning Component of Citizen-Level Science Literacy: Results from a 17,000-Student Study.

After articulating 12 concepts for the reasoning component of citizen-level science literacy and restating these as assessable student learning outcomes (SLOs), we developed a valid and reliable assessment instrument for addressing the outcomes with a brief 25-item science literacy concept inventory (SLCI). In this paper, we report the results that we obtained from assessing the citizen-level science literacy of 17,382 undergraduate students, 149 graduate students, and 181 professors. We address only findings at or above the 99.9% confidence level. We found that general education (GE) science courses do not significantly advance understanding of science as a way of knowing. However, the understanding of science's way of knowing does increase through academic ranks, indicating that the extended overall academic experience better accounts for increasing such thinking capacity than do science courses alone. Higher mean institutional SLCI scores correlate closely with increased institutional selectivity, as measured by the institutions' higher mean SAT and ACT scores. Socioeconomic factors of a) first-generation student, b) English as a native language, and c) interest in commitment to a science major are unequally distributed across ethnic groups. These factors proved powerful in accounting for the variations in SLCI scores across ethnicities and genders.

"Habits of employees": smoking, spies, and shopfloor culture at Hammermill Paper Company.

As cigarette smoking expanded dramatically during the early twentieth century, it brought more and more workers into conflict with the policies and demands of the manufacturers who employed them. As this paper shows, addiction to nicotine ignited daily struggles over workers' shopfloor rights and the ability of employers to set rules, establish discipline, and monitor behavior. A specific set of records from the archives of the Hammermill Paper Company, a paper manufacturer once based in Erie, Pennsylvania, provide a unique opportunity to explore the impact of cigarette consumption on labor relations during the era of mass production, as two nosy factory spies probed and documented worker actions and attitudes in the summer of 1915. As a result of their intelligence gathering, the spies discovered a factory-wide work culture rooted in the addictive pleasure of cigarette smoke. This discovery worried them. Worker-smokers needed to dampen their hunger for nicotine with frequent, and often clandestine, breaks from work, typically in defiance of "no-smoking" rules, employer designations for the uses of factory space, and bosses' demands for continuous production. Highlighting the intersections of the histories of labor, smoking, and addiction, this paper argues that cigarettes were a key battleground in workers' and managers' intensifying struggles over who really controlled the industrial shopfloor during the early 1900s.

Nonadditivity in the alpha-helix to coil transition.

The Lifson-Roig Model (LRM) and all its variants describe the α-helix to coil transition in terms of additive component-free energies within a free energy decomposition scheme, and these contributions are interpreted through sequence-context dependent nucleation and propagation parameters. Although this phenomenological approach is able to adequately fit experimental data on helix content and heat capacity, the number of required parameters increases dramatically with additional sequence variation. Moreover, due to nonadditive competing microscopic effects that are difficult to disentangle within a LRM, large uncertainties within the parameters emerge. We offer an alternative view that removes the need for sequence-context parameterization by focusing on individual microsopic interactions within a free energy decomposition and explicitly account for nonadditivity in conformational entropy through network rigidity using a Distance Constraint Model (DCM). We apply a LRM and a DCM to previously published experimental heat capacity and helix content data for a series of heterogeneous polypeptides. Both models describe the experimental data well, and the parameters from both models are consistent with prior work. However, the number of DCM parameters is independent of sequence-variability, the parameter values exhibit better transferability, and the helix nucleation is predicted by the DCM explicitly through the nonadditive nature of conformational entropy. The importance of these results is that the DCM offers a system-independent approach for modeling stability within polypeptides and proteins, where the demonstrated accuracy for the α-helix to coil transition over a series of heterogeneous polypeptides described here is one case in point.

Understanding the alpha-helix to coil transition in polypeptides using network rigidity: predicting heat and cold denaturation in mixed solvent conditions.

Thermodynamic stability in polypeptides is described using a novel Distance Constraint Model (DCM). Here, microscopic interactions are represented as constraints. A topological arrangement of constraints define a mechanical framework. Each constraint in the framework is associated with an enthalpic and entropic contribution. All accessible topological arrangements of distance constraints form an ensemble of mechanical frameworks, each representing a microstate of the polypeptide. A partition function is calculated exactly using a transfer matrix approach, where in many respects the DCM is similar to the Lifson-Roig model. The crucial difference is that the effect of network rigidity is explicitly calculated for each mechanical framework in the ensemble. Network rigidity is a mechanical interaction that provides a mechanism for long-range molecular cooperativity and enables a proper treatment of the nonadditivity of a microscopic free energy decomposition. Accounting for (1) helix <--> coil conformation changes along the backbone similar to the Lifson-Roig model, (2) i to i + 4 hydrogen-bond formation <--> breaking similar to the Zimm-Bragg model, and (3) structured <--> unstructured solvent interaction (hydration effects), a six-parameter DCM describes normal and inverted helix-coil transitions in polypeptides. Under suitable mixed solvent conditions heat and cold denaturation is predicted. Model parameters are fitted to experimental data showing different degrees of cold denaturation in monomeric polypeptides in aqueous hexafluoroisopropanol (HFIP) solution at various HFIP concentrations. By assuming a linear HFIP concentration dependence (up to 6% by mole fraction) on model parameters, all essential experimentally observed features are captured.