Multiscale Finite Element Modeling of Left Ventricular Growth in Simulations of Valve Disease.

Multiscale models of the cardiovascular system are emerging as effective tools for investigating the mechanisms that drive ventricular growth and remodeling. These models can predict how molecular-level mechanisms impact organ-level structure and function and could provide new insights that help improve patient care. MyoFE is a multiscale computer framework that bridges molecular and organ-level mechanisms in a finite element model of the left ventricle that is coupled with the systemic circulation. In this study, we extend MyoFE to include a growth algorithm, based on volumetric growth theory, to simulate concentric growth (wall thickening/thinning) and eccentric growth (chamber dilation/constriction) in response to valvular diseases. Specifically in our model, concentric growth is controlled by time-averaged total stress along the fiber direction over a cardiac cycle while eccentric growth responds to time-averaged intracellular myofiber passive stress over a cardiac cycle. The new framework correctly predicted different forms of growth in response to two types of valvular diseases, namely aortic stenosis and mitral regurgitation. Furthermore, the model predicted that LV size and function are nearly restored (reversal of growth) when the disease-mimicking perturbation was removed in the simulations for each valvular disorder. In conclusion, the simulations suggest that time-averaged total stress along the fiber direction and time-averaged intracellular myofiber passive stress can be used to drive concentric and eccentric growth in simulations of valve disease.

Measuring the PULSE of Nursing: Development of a Dashboard to Evaluate and Monitor Nursing Care Models.

BACKGROUND: Critical nursing shortages have required many health care organizations to restructure nursing care delivery models. At a tertiary health care center, 150 registered practical nurses were integrated into acute inpatient care settings. PROBLEM: A mechanism to continuously monitor the impact of this staffing change was not available. APPROACH: Leveraging current literature and consultation with external peers, metrics were compiled and categorized according to Donabedian's Structure Process Outcome Framework. Consultation with internal subject matter experts determined the final metrics. OUTCOMES: The Patient care, Utility, Logistics, Systemic Evaluation (PULSE) electronic dashboard was developed, capturing metrics from multiple internal databases and presenting real-time composites of validated indicators. CONCLUSION: The PULSE dashboard is a practical means of enabling nursing leadership to evaluate the impact of change and to make evidence-informed decisions about nursing care delivery at our organization.

A multiscale model of the cardiovascular system that regulates arterial pressure via closed loop baroreflex control of chronotropism, cell-level contractility, and vascular tone.

Multiscale models of the cardiovascular system can provide new insights into physiological and pathological processes. PyMyoVent is a computer model that bridges from molecular- to organ-level function and which simulates a left ventricle pumping blood through the systemic circulation. Initial work with PyMyoVent focused on the end-systolic pressure volume relationship and ranked potential therapeutic strategies by their impact on contractility. This manuscript extends the PyMyoVent framework by adding closed-loop feedback control of arterial pressure. The control algorithm mimics important features of the physiological baroreflex and was developed as part of a long-term program that focuses on growth and biological remodeling. Inspired by the underlying biology, the reflex algorithm uses an afferent signal derived from arterial pressure to drive a kinetic model that mimics the net result of neural processing in the medulla and cell-level responses to autonomic drive. The kinetic model outputs control signals that are constrained between limits that represent maximum parasympathetic and maximum sympathetic drive and which modulate heart rate, intracellular Ca2+ dynamics, the molecular-level function of both the thick and the thin myofilaments, and vascular tone. Simulations show that the algorithm can regulate mean arterial pressure at user-defined setpoints as well as maintaining arterial pressure when challenged by changes in blood volume and/or valve resistance. The reflex also regulates arterial pressure when cell-level contractility is modulated to mimic the idealized impact of myotropes. These capabilities will be important for future work that uses computer modeling to investigate clinical conditions and treatments.

Reproducibility of Systolic Strain in Mice Using Cardiac Magnetic Resonance Feature Tracking of Black-Blood Cine Images.

PURPOSE: Mouse models are widely utilized to enhance our understanding of cardiac disease. The goal of this study is to investigate the reproducibility of strain parameters that were measured in mice using cardiac magnetic resonance (CMR) feature-tracking (CMR42, Canada). METHODS: We retrospectively analyzed black-blood CMR datasets from thirteen C57BL/6 B6.SJL-CD45.1 mice (N = 10 female, N = 3 male) that were imaged previously. The circumferential, longitudinal, and radial (Ecc, Ell, and Err, respectively) parameters of strain were measured in the mid-ventricular region of the left ventricle. Intraobserver and interobserver reproducibility were assessed for both the end-systolic (ES) and peak strain. RESULTS: The ES strain had larger intraclass correlation coefficient (ICC) values when compared to peak strain, for both the intraobserver and interobserver reproducibility studies. Specifically, the intraobserver study showed excellent reproducibility for all three ES strain parameters, namely, Ecc (ICC 0.95, 95% CI 0.83-0.98), Ell (ICC 0.90, 95% CI 0.59-0.97), and Err (ICC 0.92, 95% CI 0.73-0.97). This was also the case for the interobserver study, namely, Ecc (ICC 0.92, 95% CI 0.60-0.98), Ell (ICC 0.76, 95% CI 0.33-0.93), and Err (ICC 0.93, 95% CI 0.68-0.98). Additionally, the coefficient of variation values were all < 10%. CONCLUSION: The results of this preliminary study showed excellent reproducibility for all ES strain parameters, with good to excellent reproducibility for the peak strain parameters. Moreover, all ES strain parameters had larger ICC values than the peak strain. In general, these results imply that feature-tracking with CMR42 software and black-blood cine images can be reliably used to assess strain patterns in mice.

Multiscale simulations of left ventricular growth and remodeling.

Cardiomyocytes can adapt their size, shape, and orientation in response to altered biomechanical or biochemical stimuli. The process by which the heart undergoes structural changes-affecting both geometry and material properties-in response to altered ventricular loading, altered hormonal levels, or mutant sarcomeric proteins is broadly known as cardiac growth and remodeling (G&R). Although it is likely that cardiac G&R initially occurs as an adaptive response of the heart to the underlying stimuli, prolonged pathological changes can lead to increased risk of atrial fibrillation, heart failure, and sudden death. During the past few decades, computational models have been extensively used to investigate the mechanisms of cardiac G&R, as a complement to experimental measurements. These models have provided an opportunity to quantitatively study the relationships between the underlying stimuli (primarily mechanical) and the adverse outcomes of cardiac G&R, i.e., alterations in ventricular size and function. State-of-the-art computational models have shown promise in predicting the progression of cardiac G&R. However, there are still limitations that need to be addressed in future works to advance the field. In this review, we first outline the current state of computational models of cardiac growth and myofiber remodeling. Then, we discuss the potential limitations of current models of cardiac G&R that need to be addressed before they can be utilized in clinical care. Finally, we briefly discuss the next feasible steps and future directions that could advance the field of cardiac G&R.

Force-dependent recruitment from myosin OFF-state increases end-systolic pressure-volume relationship in left ventricle.

Finite element (FE) modeling is becoming increasingly prevalent in the world of cardiac mechanics; however, many existing FE models are phenomenological and thus do not capture cellular-level mechanics. This work implements a cellular-level contraction scheme into an existing nonlinear FE code to model ventricular contraction. Specifically, this contraction model incorporates three myosin states: OFF-, ON-, and an attached force-generating state. It has been speculated that force-dependent transitions from the OFF- to ON-state may contribute to length-dependent activation at the cellular level. The current work investigates the contribution of force-dependent recruitment out of the OFF-state to ventricular-level function, specifically the Frank-Starling relationship, as seen through the end-systolic pressure-volume relationship (ESPVR). Five FE models were constructed using geometries of rat left ventricles obtained via cardiac magnetic resonance imaging. FE simulations were conducted to optimize parameters for the cellular contraction model such that the differences between FE predicted ventricular pressures for the models and experimentally measured pressures were minimized. The models were further validated by comparing FE predicted end-systolic strain to experimentally measured strain. Simulations mimicking vena cava occlusion generated descending pressure volume loops from which ESPVRs were calculated. In simulations with the inclusion of the OFF-state, using a force-dependent transition to the ON-state, the ESPVR calculated was steeper than in simulations excluding the OFF-state. Furthermore, the ESPVR was also steeper when compared to models that included the OFF-state without a force-dependent transition. This suggests that the force-dependent recruitment of thick filament heads from the OFF-state at the cellular level contributes to the Frank-Starling relationship observed at the organ level.

CAPAbility: comparison of the JOURNEY II Bi-Cruciate Stabilised and GENESIS II total knee arthroplasty in performance and functional ability: protocol of a randomised controlled trial.

BACKGROUND: Osteoarthritis of the knee is a common condition that is expected to rise in the next two decades leading to an associated increase in total knee replacement (TKR) surgery. Although there is little debate regarding the safety and efficacy of modern TKR, up to 20% of patients report poor functional outcomes following surgery. This study will investigate the functional outcome of two TKRs; the JOURNEY II Bi-Cruciate Stabilised knee arthroplasty, a newer knee prosthesis designed to provide guided motion and improve knee kinematics by more closely approximating a normal knee, and the GENESIS II, a proven existing design. AIM: To compare the change in Patient-reported Outcome Measures (PROMs) scores of the JOURNEY II BCS and the GENESIS II from pre-operation to 6 months post operation. METHODS: CAPAbility is a pragmatic, blinded, two-arm parallel, randomised controlled trial recruiting patients with primary osteoarthritis due to have unilateral TKR surgery across two UK hospitals. Eligible participants (n = 80) will be randomly allocated to receive either the JOURNEY II or the GENESIS II BCS knee prosthesis. Baseline measures will be taken prior to surgery. Patients will be followed at 1 week, 6 to 8 weeks and 6 months post-operatively. The primary outcome is the Oxford Knee Score (OKS) at 6 months post-operatively. Secondary outcomes include: other PROMs, biomechanical, radiological (computerised tomography, (CT)), clinical efficacy and safety outcomes. An embedded qualitative study will also investigate patients' perspectives via interview pre and post surgery on variables known to affect the outcome of TKR surgery. A sub-sample (n = 30) will have additional in-depth interviews to explore the themes identified. The surgeons' perspectives on the operation will be investigated by a group interview after all participants have undergone surgery. DISCUSSION: This trial will evaluate two generations of TKR using PROMS, kinematic and radiological analyses and qualitative outcomes from the patient perspective. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number Registration, ID: ISRCTN32315753. Registered on 12 December 2017.

Enhancing Nursing Capacity to Provide Patient Care in a Pandemic.

At the onset of the COVID-19 pandemic, an immediate priority for nurse leaders was to develop a care delivery plan to address anticipated surges in patient volumes and potential staff shortages. This article describes actions taken to enhance patient care capacity. Strategies included reviewing the competencies of nurses and other health professionals, mapping out redeployment pathways, preparing nurses and other health professionals for redeployment as needed and creating a collaborative care team model. This article includes an in-depth focus on the design, implementation and outcomes of an innovative role for fourth-year nursing students in the collaborative care team model.

Stiffness post-total knee replacement: A proof of principle study investigating the effect of gene expression analysis of markers of fibrosis.

BACKGROUND: To establish proof of principle of a link between phenotypic expression and stiffness after TKR. METHODS: From 100 patients, genetic expression of markers of fibrosis was performed for 15 synovial samples from patients categorised as 'best post-operative range of movement (ROM)' and 15 samples from patients with 'worst ROM'. These markers included Matrix Metalloproteinases (MMPs), A Disintegrin and Metalloproteinases with Thrombospondin (ADAMTS) and Tissue Inhibitors of Matrix Metalloproteinases (TIMPs). Genetic marker data were compared to Oxford Knee Scores (OKS) and Pain Catastrophizing Scores (PCS). RESULTS: Quantitative markers for gene expression demonstrated more outliers in stiff compared to non-stiff knees, suggesting a greater imbalance in pro- and anti-fibrotic markers in stiff knees. Whilst there was a significant difference in the range of post-operative knee flexion (p = 0.001) and extension (p = 0.001), there was no statistically significant difference between stiff and non-stiff knees in pre-operative or post-operative OKS (p ≥ 0.06). There was no difference in the individual components of the individual PCS score items nor the PCS total scores when stiff and non-stiff knees were compared (p > 0.05). CONCLUSION: Biological factors, namely gene expression of MMPs, TIMPs and ADAMTS, may contribute towards post-TKR stiffness. This now warrants further investigation to better understand this relationship based on larger, multi-centre, cohorts. LEVEL OF EVIDENCE: Level 3.

Discovery of novel selective norepinephrine inhibitors: 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides (WYE-114152).

Sequential modification of the previously identified 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols led to the identification of a new series of 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides that are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound 10b (WYE-114152) had low nanomolar hNET potency (IC(50) = 15 nM) and good selectivity for hNET over hSERT (>430-fold) and hDAT (>548-fold). 10b was additionally bioavailable following oral dosing and demonstrated efficacy in rat models of acute, inflammatory, and neuropathic pain.

Discovery of novel selective norepinephrine reuptake inhibitors: 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols (WYE-103231).

Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols which are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound S-17b (WYE-103231) had low nanomolar hNET potency (IC(50) = 1.2 nM) and excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). S-17b additionally had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain.

Synthesis and biological evaluation of piperazinyl heterocyclic antagonists of the gonadotropin releasing hormone (GnRH) receptor.

Antagonism of the gonadotropin releasing hormone (GnRH) receptor has resulted in positive clinical results in reproductive tissue disorders such as endometriosis and prostate cancer. Following the recent discovery of orally active GnRH antagonists based on a 4-piperazinylbenzimidazole template, we sought to investigate the properties of heterocyclic isosteres of the benzimidazole template. We report here the synthesis and biological activity of eight novel scaffolds, including imidazopyridines, benzothiazoles and benzoxazoles. The 2-(4-tert-butylphenyl)-8-(piperazin-1-yl)imidazo[1,2-a]pyridine ring system was shown to have nanomolar binding potency at the human and rat GnRH receptors as well as functional antagonism in vitro. Additional structure-activity relationships within this series are reported along with a pharmacokinetic comparison to the benzimidazole-based lead molecule.

Sutures versus staples for skin closure in orthopaedic surgery: meta-analysis.

OBJECTIVE: To compare the clinical outcomes of staples versus sutures in wound closure after orthopaedic surgery. DESIGN: Meta-analysis. DATA SOURCES: Medline, CINAHL, AMED, Embase, Scopus, and the Cochrane Library databases were searched, in addition to the grey literature, in all languages from 1950 to September 2009. Additional studies were identified from cited references. Selection criteria Two authors independently assessed papers for eligibility. Included studies were randomised and non-randomised controlled trials that compared the use of staples with suture material for wound closure after orthopaedic surgery procedures. All studies were included, and publications were not excluded because of poor methodological quality. Review methods Two authors independently reviewed studies for methodological quality and extracted data from each paper. Final data for analysis were collated through consensus. The primary outcome measure was the assessment of superficial wound infection after wound closure with staples compared with sutures. Relative risk and mean difference with 95% confidence intervals were calculated and pooled with a random effects model. Heterogeneity was assessed with I(2) and chi(2) statistical test. RESULTS: Six papers, which included 683 wounds, were identified; 332 patients underwent suture closure and 351 staple closure. The risk of developing a superficial wound infection after orthopaedic procedures was over three times greater after staple closure than suture closure (relative risk 3.83, 95% confidence interval 1.38 to 10.68; P=0.01). On subgroup analysis of hip surgery alone, the risk of developing a wound infection was four times greater after staple closure than suture closure (4.79, 1.24 to 18.47; P=0.02). There was no significant difference between sutures and staples in the development of inflammation, discharge, dehiscence, necrosis, and allergic reaction. The included studies had several major methodological limitations, including the recruitment of small, underpowered cohorts, poorly randomising patients, and not blinding assessors to the allocated methods of wound closure. Only one study had acceptable methodological quality. CONCLUSIONS: After orthopaedic surgery, there is a significantly higher risk of developing a wound infection when the wound is closed with staples rather than sutures. This risk is specifically greater in patients who undergo hip surgery. The use of staples for closing hip or knee surgery wounds after orthopaedic procedures cannot be recommended, though the evidence comes from studies with substantial methodological limitations. Though we advise orthopaedic surgeons to reconsider their use of staples for wound closure, definitive randomised trials are still needed to assess this research question.

Bed exercises following total hip replacement: 1 year follow-up of a single-blinded randomised controlled trial.

This paper presents the results of a study assessing whether bed exercises after primary THR (total hip replacement) improves function or quality of life, during the first post-operative year. Sixty patients undergoing primary THR were randomised to receive either a gait re-education programme and bed exercises (Group A) or a gait re-education programme without bed exercises (Group B) post-operatively. The Iowa Level of Assistance Scale (ILOA) and Short Form-12 Health Survey (SF-12) were assessed at baseline, 3 days, 6 weeks and 1 year post-operatively. There was no statistically significant difference in either ILOA or SF-12 after 1 year between Group A or B. There was no evidence of a subgroup effect by either the surgical approach or prosthesis fixation in either ILOA or SF-12.

Discovery of 6-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline (WAY-207024): an orally active antagonist of the gonadotropin releasing hormone receptor (GnRH-R).

A potent, highly insoluble, GnRH antagonist with a 2-phenyl-4-piperazinylbenzimidazole template and a quinoxaline-2,3-dione pharmacophore was modified to maintain GnRH antagonist activity and improve in vitro pharmaceutical properties. Structural changes to the quinoxaline-2,3-dione portion of the molecule resulted in several structures with improved properties and culminated in the discovery of 6-([4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl] methyl)quinoxaline (WAY-207024). The compound was shown to have excellent pharmacokinetic parameters and lowered rat plasma LH levels after oral administration.

Small molecule antagonists of the gonadotropin-releasing hormone (GnRH) receptor: structure-activity relationships of small heterocyclic groups appended to the 2-phenyl-4-piperazinyl-benzimidazole template.

A previous report described the serum LH suppression pharmacology of the 2-phenyl-4-piperazinyl-benzimidazole N-ethyluracil GnRH receptor antagonist 1 following oral administration in rats. A series of small heterocycles were appended to the 2-(4-tert-butylphenyl)-4-piperazinyl-benzimidazole template in place of the N-ethyluracil. Two imidazole analogues, 32 and 41, were shown to possess substantial in vitro potency at the target receptor (hGnRH IC(50) = 7 and 18 nM, respectively) and aqueous solubility (55 and 100 microg/mL at pH 7.4, respectively). Both compounds had high oral bioavailability in rats and 32 was further examined in an orchidectomized rat model for serum LH suppression based on increased volume of distribution over 41. Serum LH levels trended lower in orchidectomized rats following oral administration of 32.

(S)-N-(5-Chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol a Notch-1-sparing gamma-secretase inhibitor.

Accumulation of beta-amyloid (Abeta), produced by the proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase, is widely believed to be associated with Alzheimer's disease (AD). Research around the high-throughput screening hit (S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) gamma-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol 7.b.2 (Abeta(40/42) EC(50)=28 nM), which is efficacious in reduction of Abeta production in vivo.