Patient monitoring and education over a tailored digital application platform for congenital heart disease: A feasibility pilot study.

BACKGROUND: Patients with adult congenital heart disease (ACHD) are a rapidly growing cardiovascular population with increasing health needs and co-morbidities. Furthermore, their management requires frequent and ongoing hospital visits which can be burdensome. Digital health and remote monitoring have been shown to have a vast potential to enhance delivery of healthcare for patients, reducing their need for travel to clinic appointments therefore reducing costs to the patient and the healthcare service. METHODS: Patients over the age of 16 with a diagnosis of ACHD were invited to use the tailored digital application too. They were monitored for a period of 6 months. Information on patient demographics, time using the application, flagged events that prompted clinical reviews and their feedback through patient surveys were collected. RESULTS: A total of 103 patients were enrolled and registered to use the digital application tool. There were 57 (56%) males, median age at the time of enrolment was 39 (16-73) years. The majority (96%) had a moderate or complex ACHD according to the ACC/AHA classification. There was a total of 7 modules that were completed on a weekly basis. The median length of a participant session was 2.2 min and the mean time to complete a module was 21 s. In total, 35 (67%) felt that the application helped them better manage their cardiac condition. Almost all (94%) of patients expressed that they would like to continue using the application beyond the pilot. There were 18 flagged events during the 6 month observation period, and 50% of received early clinical intervention. CONCLUSION: Application based remote monitoring in this select group was well received and potentially holds large benefit to patients both clinically and economically. There were no safety concerns in our pilot feasibility study. Our data may inform much needed and timely investment in digital health.

Implementation of a mHealth solution to remotely monitor patients on a cardiac surgical waiting list: service evaluation.

BACKGROUND: The emergence of COVID-19 resulted in postponement of nonemergent surgical procedures for cardiac patients in London. mHealth represented a potentially viable mechanism for highlighting deteriorating patients on the lengthened cardiac surgical waiting lists. OBJECTIVE: To evaluate the deployment of a digital health solution to support continuous triaging of patients on a cardiac surgical waiting list. METHOD: An NHS trust utilized an app-based mHealth solution (Huma Therapeutics) to help gather vital information on patients awaiting cardiac surgery (valvular and coronary surgery). Patients at a tertiary cardiac center on a waiting list for elective surgery were given the option to be monitored remotely via a mobile app until their date of surgery. Patients were asked to enter their symptoms once a week. The clinical team monitored this information remotely, prompting intervention for those patients who needed it. RESULTS: Five hundred and twenty-five patients were on boarded onto the app. Of the 525 patients using the solution, 51 (9.71%) were identified as at risk of deteriorating based on data captured via the remote patient monitoring platform and subsequently escalated to their respective consultant. 81.7% of patients input at least one symptom after they were on boarded on the platform. DISCUSSION: Although not a generalizable study, this change in practice clearly demonstrates the feasibility and potential benefit digital remote patient monitoring can have in triaging large surgical wait lists, ensuring those that need care urgently receive it. We recommend further study into the potential beneficial outcomes from preoperative cardiac mHealth solutions.

Range-Separation Parameter in Tuned Exchange-Correlation Functionals: Successive Ionizations and the Fukui Function.

The range-separation parameter in tuned, range-separated exchange-correlation functionals is investigated in two contexts. First, the system dependence of the parameter is investigated for a series of systems obtained by successively ionizing a single species, paying particular attention to the degree of linearity in the energy versus electron number curve. The parameter exhibits significant system dependence and, therefore, achieving near-linearity in one segment of the curve leads to strong nonlinearity in other segments. This provides a challenging test case for the development of new functionals designed to overcome the known problems of this class of functional. Next, the study considers whether a range-separation parameter tuned to a Koopmans energy condition is also applicable for the analogous density condition. This is tested by comparing two formulations of the Fukui function of conceptual density functional theory, for three representative systems. Both formulations yield the same general features and are not highly sensitive to the range-separation parameter. However, the agreement between the two is near-optimal when the energy-tuned parameter is used, indicating that this parameter is applicable for the analogous density condition.

System-dependent exchange-correlation functional with exact asymptotic potential and εHOMO ≈ - I.

Density scaling considerations are used to derive an exchange-correlation explicit density functional that is appropriate for the electron deficient side of the integer and which recovers the exact r → ∞ asymptotic behaviour of the exchange-correlation potential. The functional has an unconventional mathematical form with parameters that are system-dependent; the parameters for an N-electron system are determined in advance from generalised gradient approximation (GGA) calculations on the N- and (N - 1)-electron systems. Compared to GGA results, the functional yields similar exchange-correlation energies, but HOMO energies that are an order of magnitude closer to the negative of the vertical ionisation potential; for anions, the HOMO energies are negative, as required. Rydberg excitation energies are also notably improved and the exchange-correlation potential is visibly lowered towards the near-exact potential. Further development is required to improve valence excitations, static isotropic polarisabilities, and the shape of the potential in non-asymptotic regions. The functional is fundamentally different to conventional approximations.

Assessment of Tuning Methods for Enforcing Approximate Energy Linearity in Range-Separated Hybrid Functionals.

A range of tuning methods, for enforcing approximate energy linearity through a system-by-system optimization of a range-separated hybrid functional, are assessed. For a series of atoms, the accuracy of the frontier orbital energies, ionization potentials, electron affinities, and orbital energy gaps is quantified, and particular attention is paid to the extent to which approximate energy linearity is actually achieved. The tuning methods can yield significantly improved orbital energies and orbital energy gaps, compared to those from conventional functionals. For systems with integer M electrons, optimal results are obtained using a tuning norm based on the highest occupied orbital energy of the M and M + 1 electron systems, with deviations of just 0.1-0.2 eV in these quantities, compared to exact values. However, detailed examination for the carbon atom illustrates a subtle cancellation between errors arising from nonlinearity and errors in the computed ionization potentials and electron affinities used in the tuning.

How the regulatory protein, IF(1), inhibits F(1)-ATPase from bovine mitochondria.

The structure of bovine F(1)-ATPase inhibited by a monomeric form of the inhibitor protein, IF(1), known as I1-60His, lacking most of the dimerization region, has been determined at 2.1-A resolution. The resolved region of the inhibitor from residues 8-50 consists of an extended structure from residues 8-13, followed by two alpha-helices from residues 14-18 and residues 21-50 linked by a turn. The binding site in the beta(DP)-alpha(DP) catalytic interface is complex with contributions from five different subunits of F(1)-ATPase. The longer helix extends from the external surface of F(1) via a deep groove made from helices and loops in the C-terminal domains of subunits beta(DP), alpha(DP), beta(TP), and alpha(TP) to the internal cavity surrounding the central stalk. The linker and shorter helix interact with the gamma-subunit in the central stalk, and the N-terminal region extends across the central cavity to interact with the nucleotide binding domain of the alpha(E) subunit. To form these complex interactions and penetrate into the core of the enzyme, it is likely that the initial interaction of the inhibitor with F(1) forms via the open conformation of the beta(E) subunit. Then, as two ATP molecules are hydrolyzed, the beta(E)-alpha(E) interface converts to the beta(DP)-alpha(DP) interface via the beta(TP)-alpha(TP) interface, trapping the inhibitor progressively in its binding site and a nucleotide in the catalytic site of subunit beta(DP). The inhibition probably arises by IF(1) imposing the structure and properties of the beta(TP)-alpha(TP) interface on the beta(DP)-alpha(DP) interface, thereby preventing it from hydrolyzing the bound ATP.

Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols.

The structures of F(1)-ATPase from bovine heart mitochondria inhibited with the dietary phytopolyphenol, resveratrol, and with the related polyphenols quercetin and piceatannol have been determined at 2.3-, 2.4- and 2.7-A resolution, respectively. The inhibitors bind to a common site in the inside surface of an annulus made from loops in the three alpha- and three beta-subunits beneath the "crown" of beta-strands in their N-terminal domains. This region of F(1)-ATPase forms a bearing to allow the rotation of the tip of the gamma-subunit inside the annulus during catalysis. The binding site is a hydrophobic pocket between the C-terminal tip of the gamma-subunit and the beta(TP) subunit, and the inhibitors are bound via H-bonds mostly to their hydroxyl moieties mediated by bound water molecules and by hydrophobic interactions. There are no equivalent sites between the gamma-subunit and either the beta(DP) or the beta(E) subunit. The inhibitors probably prevent both the synthetic and hydrolytic activities of the enzyme by blocking both senses of rotation of the gamma-subunit. The beneficial effects of dietary resveratrol may derive in part by preventing mitochondrial ATP synthesis in tumor cells, thereby inducing apoptosis.

Ca2+ -dependent interaction of S100A1 with F1-ATPase leads to an increased ATP content in cardiomyocytes.

S100A1, a Ca(2+)-sensing protein of the EF-hand family that is expressed predominantly in cardiac muscle, plays a pivotal role in cardiac contractility in vitro and in vivo. It has recently been demonstrated that by restoring Ca(2+) homeostasis, S100A1 was able to rescue contractile dysfunction in failing rat hearts. Myocardial contractility is regulated not only by Ca(2+) homeostasis but also by energy metabolism, in particular the production of ATP. Here, we report a novel interaction of S100A1 with mitochondrial F(1)-ATPase, which affects F(1)-ATPase activity and cellular ATP production. In particular, cardiomyocytes that overexpress S100A1 exhibited a higher ATP content than control cells, whereas knockdown of S100A1 expression decreased ATP levels. In pull-down experiments, we identified the alpha- and beta-chain of F(1)-ATPase to interact with S100A1 in a Ca(2+)-dependent manner. The interaction was confirmed by colocalization studies of S100A1 and F(1)-ATPase and the analysis of the S100A1-F(1)-ATPase complex by gel filtration chromatography. The functional impact of this association is highlighted by an S100A1-mediated increase of F(1)-ATPase activity. Consistently, ATP synthase activity is reduced in cardiomyocytes from S100A1 knockout mice. Our data indicate that S100A1 might play a key role in cardiac energy metabolism.

Inhibition sites in F1-ATPase from bovine heart mitochondria.

High-resolution crystallographic studies of a number of inhibited forms of bovine F1-ATPase have identified four independent types of inhibitory site: the catalytic site, the aurovertin B-binding site, the efrapeptin-binding site and the site to which the natural inhibitor protein IF1 binds. Hitherto, the binding sites for other inhibitors, such as polyphenolic phytochemicals, non-peptidyl lipophilic cations and amphiphilic peptides, have remained undefined. By employing multiple inhibition analysis, we have identified the binding sites for these compounds. Several of them bind to the known inhibitory sites. The amphiphilic peptides melittin and synthetic analogues of the mitochondrial import pre-sequence of yeast cytochrome oxidase subunit IV appear to mimic the natural inhibitor protein, and the polyphenolic phytochemical inhibitors resveratrol and piceatannol compete for the aurovertin B-binding site (or sites). The non-peptidyl lipophilic cation rhodamine 6G acts at a separate unidentified site, indicating that there are at least five inhibitory sites in the F1-ATPase. Each of the above inhibitors has significantly different activity against the bacterial Bacillus PS3 alpha3beta3gamma subcomplex compared with that observed with bovine F1-ATPase. IF1 does not inhibit the bacterial enzyme, even in the absence of the epsilon-subunit. An understanding of these inhibitors may enable rational development of therapeutic agents to act as novel antibiotics against bacterial ATP synthases or for the treatment of several disorders linked to the regulation of the ATP synthase, including ischaemia-reperfusion injury and some cancers.