Radioproteomics stratifies molecular response to antifibrotic treatment in pulmonary fibrosis.

Antifibrotic therapy with nintedanib is the clinical mainstay in the treatment of progressive fibrosing interstitial lung disease (ILD). High-dimensional medical image analysis, known as radiomics, provides quantitative insights into organ-scale pathophysiology, generating digital disease fingerprints. Here, we used an integrative analysis of radiomic and proteomic profiles (radioproteomics) to assess whether changes in radiomic signatures can stratify the degree of antifibrotic response to nintedanib in (experimental) fibrosing ILD. Unsupervised clustering of delta radiomic profiles revealed two distinct imaging phenotypes in mice treated with nintedanib, contrary to conventional densitometry readouts, which showed a more uniform response. Integrative analysis of delta radiomics and proteomics demonstrated that these phenotypes reflected different treatment response states, as further evidenced on transcriptional and cellular levels. Importantly, radioproteomics signatures paralleled disease- and drug related biological pathway activity with high specificity, including extracellular matrix (ECM) remodeling, cell cycle activity, wound healing, and metabolic activity. Evaluation of the preclinical molecular response-defining features, particularly those linked to ECM remodeling, in a cohort of nintedanib-treated fibrosing ILD patients, accurately stratified patients based on their extent of lung function decline. In conclusion, delta radiomics has great potential to serve as a non-invasive and readily accessible surrogate of molecular response phenotypes in fibrosing ILD. This could pave the way for personalized treatment strategies and improved patient outcomes.

Road-Map to Epicardial Approach for Catheter Ablation of Ventricular Tachycardia in Structural Heart Disease: Results From a 10-Year Tertiary-Center Experience.

BACKGROUND: Epicardial approach in ventricular tachycardia (VT) ablation is still regarded as a second-step strategy, due to the risk of complications. We evaluated the frequency that epicardial ablation targets were identified and ablation performed following pericardial access compared with unnecessary pericardial access for different VT causes and potential markers of epicardial VT. METHODS: All VT ablation procedures including epicardial approach over a 10-year period were included. First-line epicardial approach was indicated in arrhythmogenic right ventricular cardiomyopathy (ARVC) and postmyocarditis VT; in patients with idiopathic dilated cardiomyopathy (IDCM) and postmyocardial infarction, indications resulted from available imaging techniques or 12-lead VT morphology. The epicardial approach was considered useful if epicardial ablation was performed after epicardial mapping. Feasibility, complications, and long-term outcome were reported. RESULTS: Four hundred and eighty-eight subjects with a median age of 60 years (interquartile range, 47-65) and of left ventricle ejection fraction 41% (interquartile range, 30-55) underwent 626 epicardial VT ablations. Percutaneous access had a success rate of 92.2% and a complication rate of 3.6%. Overall, epicardial approach was, respectively, indicated to 11.8% of postmyocardial infarction patients, 49.5% in IDCM, 94% in myocarditis, and 90.7% in ARVC. Epicardial ablation at the first ablation attempt was performed in 9.3% of postmyocardial infarction patients, 28.8% in IDCM, 86.5% in myocarditis, and 81.3% in patients with ARVC. In first-line epicardial group, ARVC and myocarditis showed the highest odds for epicardial ablation (OR, 4.057 [95% CI, 1.299-8.937]; P=0.007; OR, 3.971 [95% CI, 1.376-11.465]; P=0.005, respectively). IDCM independently predicted unnecessary epicardial approach (OR, 2.7 [95% CI, 1.7-4.3]; P<0.001). After a follow-up of 41 months (interquartile range, 19-64), patients with IDCM experienced higher rate of recurrences and mortality compared with other causes. CONCLUSIONS: Epicardial approach is integral part of ablation armamentarium regardless of the VT cause, with high feasibility and low complication rate in experienced centers. Our data support its use at first ablation attempt in VTs related to ARVC and myocarditis.

Tailored and Externally Corrected Coupled Cluster with Quantum Inputs.

We propose to use wave function overlaps obtained from a quantum computer as inputs for the classical split-amplitude techniques, tailored and externally corrected coupled cluster, to achieve balanced treatment of static and dynamic correlation effects in molecular electronic structure simulations. By combining insights from statistical properties of matchgate shadows, which are used to measure quantum trial state overlaps, with classical correlation diagnostics, we can provide quantum resource estimates well into the classically no longer exactly solvable regime. We find that rather imperfect wave functions and remarkably low shot counts are sufficient to cure qualitative failures of plain coupled cluster singles doubles and to obtain chemically precise dynamic correlation energy corrections. We provide insights into which wave function preparation schemes have a chance of yielding quantum advantage, and we test our proposed method using overlaps measured on Google's Sycamore device.

Estimation of Electrostatic Interaction Energies on a Trapped-Ion Quantum Computer.

We present the first hardware implementation of electrostatic interaction energies by using a trapped-ion quantum computer. As test system for our computation, we focus on the reduction of NO to N2O catalyzed by a nitric oxide reductase (NOR). The quantum computer is used to generate an approximate ground state within the NOR active space. To efficiently measure the necessary one-particle density matrices, we incorporate fermionic basis rotations into the quantum circuit without extending the circuit length, laying the groundwork for further efficient measurement routines using factorizations. Measurements in the computational basis are then used as inputs for computing the electrostatic interaction energies on a classical computer. Our experimental results strongly agree with classical noise-less simulations of the same circuits, finding electrostatic interaction energies within chemical accuracy despite hardware noise. This work shows that algorithms tailored to specific observables of interest, such as interaction energies, may require significantly fewer quantum resources than individual ground state energies would require in the straightforward supermolecular approach.

Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy.

OBJECTIVE: Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that the pretreatment molecular profiles of diagnostic biopsies can predict patient benefit from chemotherapy and define molecular bases of innate chemoresistance. DESIGN: We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as extreme outliers on chemotherapy (survival <6 m in rapid progressors, RP; survival >23 m in long survivors, LS). Diagnostic biopsies were characterised by digital pathology, then subjected to whole-transcriptome profiling of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumour-infiltrating myeloid cells was performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in multiple cohorts of resected cancers. Signatures were also characterised using in vitro cell lines, in vivo mouse models and single cell RNA-sequencing data. RESULTS: Pretreatment transcriptome profiles differentiated patients who would become RPs or LSs on chemotherapy. Biologically, this signature originated from altered tumour-myeloid dynamics, implicating tumour-induced immune tolerogenicity with poor response to chemotherapy. The central role of the liver microenviroment was confrmed by the association of the RPLS transcriptome signature with clinical outcome in iCCA but not extrahepatic CCA, and in liver metastasis from colorectal cancer, but not in the matched primary bowel tumours. CONCLUSIONS: The RPLS signature could be a novel metric of chemotherapy outcome in iCCA. Further development and validation of this transcriptomic signature is warranted to develop precision chemotherapy strategies in these settings.

PICKLUSTER: a protein-interface clustering and analysis plug-in for UCSF ChimeraX.

SUMMARY: The identification and characterization of interfaces in protein complexes is crucial for understanding the mechanisms of molecular recognition. These interfaces are also attractive targets for protein inhibition. However, targeting protein interfaces can be challenging for large interfaces that consist of multiple interacting regions. We present PICKLUSTER [Protein Interface C(K)luster]-a program for identifying "sub-interfaces" in protein-protein complexes using distance clustering. The division of the interface into smaller "sub-interfaces" offers a more focused approach for targeting protein-protein interfaces. AVAILABILITY AND IMPLEMENTATION: PICKLUSTER is implemented as a plug-in for the molecular visualization program UCSF ChimeraX 1.4 and subsequent versions. It is freely available for download in the ChimeraX Toolshed and https://gitlab.com/topf-lab/pickluster.git.

Efficient quantum analytic nuclear gradients with double factorization.

Efficient representations of the Hamiltonian, such as double factorization, drastically reduce the circuit depth or the number of repetitions in error corrected and noisy intermediate-scale quantum (NISQ) algorithms for chemistry. We report a Lagrangian-based approach for evaluating relaxed one- and two-particle reduced density matrices from double factorized Hamiltonians, unlocking efficiency improvements in computing the nuclear gradient and related derivative properties. We demonstrate the accuracy and feasibility of our Lagrangian-based approach to recover all off-diagonal density matrix elements in classically simulated examples with up to 327 quantum and 18 470 total atoms in QM/MM simulations with modest-sized quantum active spaces. We show this in the context of the variational quantum eigensolver in case studies, such as transition state optimization, ab initio molecular dynamics simulation, and energy minimization of large molecular systems.

Left atrial appendage closure: a new strategy for cardioembolic events despite oral anticoagulation.

BACKGROUND: Patients with non-valvular atrial fibrillation (nvAF) who experienced a cardioembolic (CE) event despite adequate oral anticoagulation (OAC) are at high risk of recurrence, and further prevention strategies are deemed necessary. The present study aimed to evaluate the safety and efficacy of off-label use of left atrial appendage closure (LAAC) in this subset of patients. METHODS: Seventy-five consecutive patients with nvAF who experienced a CE event despite adequate OAC therapy were retrospectively enrolled from two Italian centers. Patients were divided according to the treatment strategy following the index event: DOAC group (49 patients who continued OAC therapy with DOACs) and LAAC group (26 patients who underwent LAAC procedure). 1:1 propensity-score matching between the two groups was performed. LAAC group was made up of two subgroups according to the post-procedural pharmacological regimen: 1) dual antiplatelet therapy (DAPT) for 3 months followed by indefinite single antiplatelet therapy (LAAC+SAPT); or 2) aspirin plus DOAC for 3 months followed by indefinite DOAC therapy (LAAC+DOAC). The primary endpoint was a composite of CE event, major bleeding, or procedure-related major complication. RESULTS: During a median follow-up of 3.4 years (IQR: 2.0-5.3), LAAC was a predictor of primary endpoint-free survival (HR=0.28, 95% CI: 0.08-0.97; P=0.044); within LAAC group, no procedure-related major complication occurred. Moreover, a trend toward a lower rate of both CE events and major bleedings was observed in LAAC group, particularly in the subgroup LAAC+DOAC. CONCLUSIONS: LAAC is a reasonable therapeutic option in nvAF patients who suffered a CE event despite adequate OAC therapy.

Step by Step through the Years-High vs. Low Energy Lead Extraction Using Advanced Extraction Techniques.

Background: Limited data is available about the outcome of TLE in patients with vs. without high energy leads in the last decade. Methods: This is an analysis of consecutive patients undergoing TLE at a high-volume TLE centre from 2001 to 2021 using the stepwise approach. Baseline characteristics, procedural details and outcome of patients with high energy lead (ICD group) vs. without high energy lead (non-ICD group) were compared. Results: Out of 667 extractions, 991 leads were extracted in 405 procedures (60.7%) in the ICD group and 439 leads in 262 procedures (39.3%) in the non-ICD group. ICD patients were significantly younger (median 67 vs. 74 years) and were significantly less often female (18.1% vs. 27.7%, p < 0.005 for both). Advanced extraction tools were used significantly more often in the ICD group (73.2% vs. 37.5%, p < 0.001), but there were no significant differences in the successful removal (98.8% vs. 99.2%) or complications (4.7% vs. 3.1%) between the groups (p > 0.2 for both). Discussion: Using the stepwise approach, overall procedural success was high and complication rate was low in a high-volume centre. In patients with a high energy lead, the TLE procedure was more complex, but outcome was similar to comparator patients.

Working on the dirty side-the ipsilateral subclavian access for temporary pacing after lead extraction.

Background: Temporary pacing is necessary in pacemaker-dependent patients after transvenous lead extraction (TLE) for cardiac implantable electronic device infection. In case of unavailability of other accesses, we propose to use the ipsilateral subclavian access (ISA) combined with a standard permanent active fixation lead for the temporary pacemaker and present preliminary data. Methods: We consecutively enrolled patients undergoing TLE who received a temporary pacemaker using the ISA between August 2016 and April 2020 at our centre. Results: During the observation period, 36 patients undergoing TLE for pocket infection (72.2%), endocarditis (25.0%) or other causes received a temporary pacemaker over the ISA. Their mean age was 77.0 ± 10.7 years, and 13.9% were female. Complete TLE was achieved in 94.4%. There were no major periprocedural complications. Intra-hospital mortality was 11.1%. Pocket revision was performed in 19.4%. During long-term follow-up (23 ± 13 months), 8.3% had a relapse of local pocket infection and 2.8% needed rehospitalization for reintervention. Conclusions: Temporary pacing using a standard permanent active fixation lead using the ISA is a convenient alternative to conventional venous accesses. However, risks of implanting a lead into a previously infected area have to be taken into account.

Cool birds: first evidence of energy-saving nocturnal torpor in free-living common swifts Apus apus resting in their nests.

Daily torpor is a means of saving energy by controlled lowering of the metabolic rate (MR) during resting, usually coupled with a decrease in body temperature. We studied nocturnal daily torpor under natural conditions in free-living common swifts Apus apus resting in their nests as a family using two non-invasive approaches. First, we monitored nest temperature (Tnest) in up to 50 occupied nests per breeding season in 2010-2015. Drops in Tnest were the first indication of torpor. Among 16 673 observations, we detected 423 events of substantial drops in Tnest of on average 8.6°C. Second, we measured MR of the families inside nest-boxes prepared for calorimetric measurements during cold periods in the breeding seasons of 2017 and 2018. We measured oxygen consumption and carbon dioxide production using a mobile indirect respirometer and calculated the percentage reduction in MR. During six torpor events observed, MR was gradually reduced by on average 56% from the reference value followed by a decrease in Tnest of on average 7.6°C. By contrast, MR only decreased by about 33% on nights without torpor. Our field data gave an indication of daily torpor, which is used as a strategy for energy saving in free-living common swifts.

Non-pegylated liposomal doxorubicin plus cyclophosphamide as first-line therapy in elderly women with HER2 negative metastatic breast cancer.

Background: The use of anthracyclines in metastatic breast cancer (MBC) is limited by cumulative dose-dependent cardiotoxicity mostly in elderly women with comorbidities. The aim of this observational retrospective study was to evaluate the efficacy of non-pegylated liposomal doxorubicin (Myocet®) and cyclophosphamide in elderly women as HER2 negative first-line MBC treatment. Methods: 84 elderly women >70 years of age (median age 78 years) with MBC HER2 negative were enrolled. Performance Status in 58 patients was ECOG-0 and in 26 patients was ECOG-1. Results: The drug was well tolerated, with overall response rates were >40%, median overall survival was 16.2 months (95%CI:14.6-18.8) and median progression free survival was 5.8 months (95%CI:4.4-8.6). Hematologic toxicity with neutropenia was the most frequent adverse event, but the treatment was well tolerated maintained a manageable cardiotoxicity. Conclusion: Non-pegylated liposomal doxorubicin may represent a valid therapeutic option in first-line for elderly patients with HER/2 negative MBC improving survival, anti-tumor response rate and de-creases cardiotoxicity.

Tachykinins amplify the action of capsaicin on central histaminergic neurons.

Substance P (SP), a product of the tachykinin 1 (Tac1) gene, is expressed in many hypothalamic neurons. Its wake-promoting potential could be mediated through histaminergic (HA) neurons of the tuberomamillary nucleus (TMN), where functional expression of neurokinin receptors (NKRs) waits to be characterized. As in the process of nociception in the peripheral nervous system (PNS) capsaicin-receptor (transient potential vanilloid 1: TRPV1) signalling is amplified by local release of histamine and SP, we tested the involvement of tachykinins in the capsaicin-induced long-lasting enhancement (LLEcaps) of HA neurons firing by investigating selective neurokinin receptor ligands in the hypothalamic mouse brain slice preparation using patch-clamp recordings in cell-attached mode combined with single-cell RT-PCR. We report that the majority of HA neurons respond to SP (EC50 3 nM), express the SP precursor tachykinin 1 (Tac1) gene and at least one of the neurokinin receptors. Responses to selective agonists of three known neurokinin receptors were sensitive to corresponding antagonists. LLEcaps was significantly impaired by the neurokinin receptor antagonists, indicating that in hypothalamus, as in the PNS, release of tachykinins downstream to TRPV1 activation is able to boost the release of histamine. The excitatory action of SP on histaminergic neurons adds another pathway to the noradrenergic and orexinergic ones to synergistically enhance cortical arousal. We show NK1R to play a prominent role on HA neurons and thus the control of wakefulness.

Prognostic implications of different clinical profiles in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a myocardial genetic disease relatively common in the general population with heterogenous clinical presentation, natural history and prognosis. About 60% of HCM patients have a stable clinical course, while others may experience a variety of HCM-related complications which follows relatively independent pathways, and that can be distinguished in different subgroups. These subgroups are represented by patients with left ventricular outflow tract obstruction; patients with end-stage disease and reduced or preserved systolic function; patients with apical hypertrophy; patients with apical aneurysm; patients with atrial fibrillation, patients at high risk of sudden death and patients with preclinical HCM. The purpose of this review was to describe each of these clinical profiles with its prognostic implications.

Measuring and Modelling Nonlinear Elasticity of Ex Vivo Mouse Muscles.

Elastography is a noninvasive imaging technique that provides information on soft tissue stiffness. Young's modulus is typically used to characterize soft tissues' response to the applied force, as soft tissues are often considered linear elastic, isotropic, and quasi-incompressible materials. This approximation is reasonable for small strains, but soft tissues undergo large deformations also for small values of force and exhibit nonlinear elastic behavior. Outside the linear regime, the elastic modulus is dependent on the strain level and is different for any kind of tissue. The aim of this study was to characterize, ex vivo, the mechanical response of two different mice muscles to an external force. A system for transverse force-controlled uniaxial compression enabled obtaining the stress-strain (σ-ε) curve of the samples. The strain-dependent Young's modulus (SYM) model was adopted to reproduce muscle compression behavior and to predict the elastic modulus for large deformations. After that, a recursive linear model was employed to identify the initial linear region of the σ-ε curve. Results showed that both muscle types exhibited a strain hardening effect and that the SYM model provided good fitting of the entire σ-ε curves. The application of the recursive linear model allowed capturing the initial linear region in which the approximation of these tissues as linear elastic materials is reasonable. The residual analysis displayed that even if the SYM model better summarizes the muscle behavior on the entire region, the linear model is more precise when considering only the initial part of the σ-ε curve.

NEPA (netupitant/palonosetron) for the antiemetic prophylaxis of nausea and vomiting induced by chemotherapy (CINV) with Folfirinox and Folfoxiri even during the COVID-19 pandemic: a real-life study.

OBJECTIVE: The outbreak of coronavirus disease 2019 (COVID-19) has affected the treatment of cancer patients, with particular regard to the management of both chemotherapy and side effects. Chemotherapy-induced nausea and vomiting (CINV) are amongst the most troublesome side effects that impair patients' adherence to treatments and their quality of life (QoL). NEPA (Akynzeo®), is an oral fixed-dose combination of netupitant [a neurokinin-1 receptor antagonist (NK1RA), 300 mg] and palonosetron [(5-hydroxytryptamine (serotonin or 5HT) type3 receptor antagonist (5HT3RA), 0.5 mg] which has been shown to be effective in preventing CINV. PATIENTS AND METHODS: This prospective study started before the outbreak of COVID-19 and was carried out during the pandemic period. The aim was to evaluate the efficacy and safety of a single oral dose NEPA plus 12 mg of dexamethasone (DEX) in patients treated with Folfoxiri plus Bevacizumab and Folfirinox. The patients were diagnosed with advanced colorectal cancer (CRC) or advanced pancreatic ductal adenocarcinoma (PDAC). They were divided into two groups: naïve patients and patients previously treated with serotonin receptor antagonists (5HT3-RA) and neurokin-1 receptor antagonists (NK1-RA). RESULTS: During the overall phase, the complete response (CR) rate was 96.8% in naïve patients treated with Folfoxiri plus Bevacizumab, and 94.6% in patients treated with Folfirinox. During the acute and delayed phases, the CR rate was 92.8% and 94.2%, with Folfoxiri and Bevacizumab, as well as 96.2% and 94.6%, with Folfirinox. There was no adequate control of CINV events in patients on antiemetic prophylaxis with 5HT3-RA or NK1-RA associated with cortisone. During the overall phase, the CR rate was 74.6% with Folfoxiri plus Bevacizumab and 75.8% with Folfirinox. During the acute and delayed phases, the CR rate was 72.5% and 74.8% with Folfoxiri plus Bevacizumab, as well as 75.2% and 74.6% with Folfirinox. CONCLUSIONS: This study has shown the therapeutic benefits of NEPA in the management and prophylaxis of CINV events, both in naive patients and patients previously treated with 5HT3-RA and NK1-RA. In addition, NEPA has been shown to be safe, both before and during the COVID-19 pandemic.

Reliability assessment of temporal discounting measures in virtual reality environments.

In recent years the emergence of high-performance virtual reality (VR) technology has opened up new possibilities for the examination of context effects in psychological studies. The opportunity to create ecologically valid stimulation in a highly controlled lab environment is especially relevant for studies of psychiatric disorders, where it can be problematic to confront participants with certain stimuli in real life. However, before VR can be confidently applied widely it is important to establish that commonly used behavioral tasks generate reliable data within a VR surrounding. One field of research that could benefit greatly from VR-applications are studies assessing the reactivity to addiction related cues (cue-reactivity) in participants suffering from gambling disorder. Here we tested the reliability of a commonly used temporal discounting task in a novel VR set-up designed for the concurrent assessment of behavioral and psychophysiological cue-reactivity in gambling disorder. On 2 days, thirty-four healthy non-gambling participants explored two rich and navigable VR-environments (neutral: café vs. gambling-related: casino and sports-betting facility), while their electrodermal activity was measured using remote sensors. In addition, participants completed the temporal discounting task implemented in each VR environment. On a third day, participants performed the task in a standard lab testing context. We then used comprehensive computational modeling using both standard softmax and drift diffusion model (DDM) choice rules to assess the reliability of discounting model parameters assessed in VR. Test-retest reliability estimates were good to excellent for the discount rate log(k), whereas they were poor to moderate for additional DDM parameters. Differences in model parameters between standard lab testing and VR, reflecting reactivity to the different environments, were mostly numerically small and of inconclusive directionality. Finally, while exposure to VR generally increased tonic skin conductance, this effect was not modulated by the neutral versus gambling-related VR-environment. Taken together this proof-of-concept study in non-gambling participants demonstrates that temporal discounting measures obtained in VR are reliable, suggesting that VR is a promising tool for applications in computational psychiatry, including studies on cue-reactivity in addiction.

Use of Eribulin mesylate as second-line therapy in elderly patients with HER/2 negative metastatic breast cancer (MBC): efficacy, tolerability and Quality of Life.

OBJECTIVE: Eribulin mesylate (Halaven®) is a non-taxane inhibitor of microtubule indicated as monotherapy in patients with metastatic breast cancer (MBC), which progresses after anthracycline and taxanes therapy. In this retrospective observational study, we want to evaluate the efficacy of Eribulin in elderly women with MBC pretreated with anthracyclines and taxanes. PATIENTS AND METHODS: 40 elderly patients > 70 years of age were enrolled, and the median age was 76 years (range 70-82). Overall survival (OS), Progression Free Survival (PFS), Objective Response Rate (ORR) were primary endpoints, tolerability, carcinoembryonic antigen levels 15.3 (Ca 15.3), before and after treatment, and Quality of Life (QoL) were secondary endpoints. RESULTS: Eribulin treatment was well tolerated, produced a good level of disease control, a manageable toxicity profile and a significant impact on QoL. Median OS was 12.8 months and median PFS was 3.2 months. A significant correlation was observed between reduction of Ca 15.3 and PFS with a value of 0.59 (p = 0.002). CONCLUSIONS: Despite a limited number of patients and a modest manageable toxicity, Eribulin is a chemotherapy treatment that has showed to be an effective and well-tolerated therapeutic option in elderly patients with MBC. Further analysis should focus on the elderly patients in our setting of study.

Memory effects and self-excited oscillations in deterministic epidemic models with intrinsic time delays.

The simplest delay differential equation describing the dynamics of non-lethal infectious diseases in a fixed-size population is extended to include the incubation period, as an additional delay parameter. It is observed that these types of deterministic models consist of one delay differential equation, whereas standard SIR and SEIR models consist of two and three ordinary differential equations, respectively. The extended model presents interesting peculiarities as, for example, initial oscillatory patterns in the curve counting the infectious individuals. A comparison of the doubly delayed differential equation with the standard SEIR model is made. It is argued that self-sustained oscillations, which are intrinsic properties of models with time delay, have to be taken into account in designing optimal epidemic containment strategies.