A Mathematical Model for Interpretable Clinical Decision Support with Applications in Gynecology

Over time, methods for the development of clinical decision support (CDS) systems have evolved from interpretable and easy-to-use scoring systems to very complex and non-interpretable mathematical models. In order to accomplish effective decision support, CDS systems should provide information on how the model arrives at a certain decision. To address the issue of incompatibility between performance, interpretability and applicability of CDS systems, this paper proposes an innovative model structure, automatically leading to interpretable and easily applicable models. The resulting models can be used to guide clinicians when deciding upon the appropriate treatment, estimating patient-specific risks and to improve communication with patients.We propose the interval coded scoring (ICS) system, which imposes that the effect of each variable on the estimated risk is constant within consecutive intervals. The number and position of the intervals are automatically obtained by solving an optimization problem, which additionally performs variable selection. The resulting model can be visualised by means of appealing scoring tables and color bars. ICS models can be used within software packages, in smartphone applications, or on paper, which is particularly useful for bedside medicine and home-monitoring. The ICS approach is illustrated on two gynecological problems: diagnosis of malignancy of ovarian tumors using a dataset containing 3,511 patients, and prediction of first trimester viability of pregnancies using a dataset of 1,435 women. Comparison of the performance of the ICS approach with a range of prediction models proposed in the literature illustrates the ability of ICS to combine optimal performance with the interpretability of simple scoring systems.The ICS approach can improve patient-clinician communication and will provide additional insights in the importance and influence of available variables. Future challenges include extensions of the proposed methodology towards automated detection of interaction effects, multi-class decision support systems, prognosis and high-dimensional data

Probing exotic phenomena at the interface of nuclear and particle physics with the electric dipole moments of diamagnetic atoms: A unique window to hadronic and semi-leptonic CP violation

The current status of electric dipole moments of diamagnetic atoms which involves the synergy between atomic experiments and three different theoretical areas -- particle, nuclear and atomic is reviewed. Various models of particle physics that predict CP violation, which is necessary for the existence of such electric dipole moments, are presented. These include the standard model of particle physics and various extensions of it. Effective hadron level combined charge conjugation (C) and parity (P) symmetry violating interactions are derived taking into consideration different ways in which a nucleon interacts with other nucleons as well as with electrons. Nuclear structure calculations of the CP-odd nuclear Schiff moment are discussed using the shell model and other theoretical approaches. Results of the calculations of atomic electric dipole moments due to the interaction of the nuclear Schiff moment with the electrons and the P and time-reversal (T) symmetry violating tensor-pseudotensor electron-nucleus are elucidated using different relativistic many-body theories. The principles of the measurement of the electric dipole moments of diamagnetic atoms are outlined. Upper limits for the nuclear Schiff moment and tensor-pseudotensor coupling constant are obtained combining the results of atomic experiments and relativistic many-body theories. The coefficients for the different sources of CP violation have been estimated at the elementary particle level for all the diamagnetic atoms of current experimental interest and their implications for physics beyond the standard model is discussed. Possible improvements of the current results of the measurements as well as quantum chromodynamics, nuclear and atomic calculations are suggested.Comment: 46 pages, 19 tables and 16 figures. A review article accepted for EPJ

The L 98-59 System: Three Transiting, Terrestrial-Size Planets Orbiting A Nearby M Dwarf

We report the Transiting Exoplanet Survey Satellite (TESS) discovery of three terrestrial-size planets transiting L 98-59 (TOI-175, TIC 307210830)—a bright M dwarf at a distance of 10.6 pc. Using the Gaia-measured distance and broadband photometry, we find that the host star is an M3 dwarf. Combined with the TESS transits from three sectors, the corresponding stellar parameters yield planet radii ranging from 0.8 R⊕ to 1.6 R⊕. All three planets have short orbital periods, ranging from 2.25 to 7.45 days with the outer pair just wide of a 2:1 period resonance. Diagnostic tests produced by the TESS Data Validation Report and the vetting package DAVE rule out common false-positive sources. These analyses, along with dedicated follow-up and the multiplicity of the system, lend confidence that the observed signals are caused by planets transiting L 98-59 and are not associated with other sources in the field. The L 98-59 system is interesting for a number of reasons: the host star is bright (V = 11.7 mag, K = 7.1 mag) and the planets are prime targets for further follow-up observations including precision radial-velocity mass measurements and future transit spectroscopy with the James Webb Space Telescope; the near-resonant configuration makes the system a laboratory to study planetary system dynamical evolution; and three planets of relatively similar size in the same system present an opportunity to study terrestrial planets where other variables (age, metallicity, etc.) can be held constant. L 98-59 will be observed in four more TESS sectors, which will provide a wealth of information on the three currently known planets and have the potential to reveal additional planets in the system

The L 98-59 System: Three Transiting, Terrestrial-size Planets Orbiting a Nearby M Dwarf

We report the Transiting Exoplanet Survey Satellite (TESS) discovery of three terrestrial-size planets transiting L 98-59 (TOI-175, TIC 307210830)—a bright M dwarf at a distance of 10.6 pc. Using the Gaia-measured distance and broadband photometry, we find that the host star is an M3 dwarf. Combined with the TESS transits from three sectors, the corresponding stellar parameters yield planet radii ranging from 0.8 R ⊕ to 1.6 R ⊕. All three planets have short orbital periods, ranging from 2.25 to 7.45 days with the outer pair just wide of a 2:1 period resonance. Diagnostic tests produced by the TESS Data Validation Report and the vetting package DAVE rule out common false-positive sources. These analyses, along with dedicated follow-up and the multiplicity of the system, lend confidence that the observed signals are caused by planets transiting L 98-59 and are not associated with other sources in the field. The L 98-59 system is interesting for a number of reasons: the host star is bright (V = 11.7 mag, K = 7.1 mag) and the planets are prime targets for further follow-up observations including precision radial-velocity mass measurements and future transit spectroscopy with the James Webb Space Telescope; the near-resonant configuration makes the system a laboratory to study planetary system dynamical evolution; and three planets of relatively similar size in the same system present an opportunity to study terrestrial planets where other variables (age, metallicity, etc.) can be held constant. L 98-59 will be observed in four more TESS sectors, which will provide a wealth of information on the three currently known planets and have the potential to reveal additional planets in the system

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570