Parent Positive, can reverse the negative effects of the pandemic on children and parents. The efficacy on child and parent outcomes and cost-effectiveness of Parent Positive will be examined. We will also test whether the effects are moderated by pre-existing levels of child conduct problems and usage of Parent Positive. Exploratory analyses will examine whether other baseline characteristics or lockdown circumstances moderate the effects of Parent Positive.The COVID-19 related lockdowns and distancing measures have presented families with unprecedented challenges. A UK-wide cohort study tracking changes in families’ mental health since early lockdown (Co-SPACE) found a significant rise in primary school-aged children’s behaviour problems and associated family-related stress. Three-quarters of parents in Co-SPACE also reported wanting extra support. In SPARKLE, we will examine whether providing Co-SPACE families with a smartphone application delivering information and parenting support, Parent Positive or Follow-up As Usual (FAU).SPARKLE is a two-arm superiority parallel group randomised controlled trial embedded in an existing large UK-wide self-selected community cohort – Co-SPACE. Those who consent to SPARKLE will be randomised 1:1 to either Co-SPACE  parents aged ≥18 who have children aged 4-10 years will be eligible for SPARKLE.Parent Positive: is a digital public health intervention that can be delivered rapidly at scale to support parents in managing their children’s behaviour to reduce conduct problems and levels of family conflict, which were exacerbated during the first lockdown, and which may increase further in future months as families need to cope with continuous uncertainty and further disruption to their daily lives. Co-designed with parents and based on decades of parenting research, Parent Positive consists of three elements: (i) Parenting Boosters: where advice, delivered in the form of narrated animations, videos, graphics and text is provided to help parents with eight common parenting challenges; (ii) Parenting Exchange: a facilitated parent-to-parent communication and peer support platform and; (iii) Parent Resources: giving access to carefully selected high-quality, evidence-based online parenting resources.Follow-up as Usual: FAU was selected as a comparator because the public health nature meant that an active comparator was not appropriate due to the pragmatic, rapid implementation of the trial. Individuals randomised to FAU will receive no intervention for the first two months while the data for baseline (T1), T2 and T3 are collected. They will then be given full access to the app until 30th November 2021.Outcome measures will be collected remotely through Qualtrics according to the Co-SPACE schedule at baseline (T1), which will be the Co-SPACE survey data obtained immediately prior to randomisation, and then at one month (T2) and two months (T3) post-randomisation. Measures will be collected to assess group differences in child and parent outcomes, costs and service utilisation, and adverse events. Usage of Parent Positive will also be tracked. The primary outcome is parent-reported child conduct problems at one-month post-randomisation measured using the Strengths and Difficulties Questionnaire conduct problems subscale.Parent Positive or FAU at the ratio of 1:1 by simple randomisation using the Randomizer function within the Qualtrics programme. Neither blocking nor stratification will be used.Enrolled participants will be allocated to It is not possible to blind parents enrolled in the study and Qualtrics will automatically inform parents of their group allocation. Blinded members of the research team and the senior statistician will not be given access to the Qualtrics system or the data in order to remain blinded until after the analysis is complete. We do not anticipate any serious harms associated with taking part in the intervention, therefore there will be no need to unblind any blinded staff during the study. The junior statistician will be unblinded throughout.A total of 616 will be recruited into the trial with 308 consenting parents randomised to each treatment arm.st April 2021. Anticipated end date for recruitment: 31st July 2021.V1.0; 15.03.2021. Not yet recruiting. Anticipated start date: 1NCT04786080. The trial was prospectively registered on 8 March 2021.Clinicaltrial.gov: The full protocol is attached as an additional file, accessible from the Trials website (Additional file The online version contains supplementary material available at 10.1186/s13063-021-05226-4. Additional file 1. Full Study Protocol.Additional file 2. SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents.


A 79-year-old man suddenly developed right lower extremity (RLE) pain and swelling a few days after receiving his 1st dose of the mRNA-1273 COVID-19 vaccine. Despite this, he proceeded to receive the 2nd dose of his mRNA-1273 COVID-19 vaccine. Investigations confirmed extensive acute deep venous thrombosis and a concurrent acute pulmonary embolism. Therapeutic anticoagulation was initiated and he was eventually discharged home on supplemental oxygen. The overall benefits of the vaccine in curbing severe disease overwhelmingly outweigh the handful of cases of reported adverse events. To our knowledge, this is one of the first few cases of provoked venous thrombosis after receiving the mRNA-1273 COVID-19 vaccine during the pharmacovigilance period. The coronavirus disease 2019 (COVID-19) has reached catastrophic levels - over 359 million global cases and 5.6 million deaths by the end of January 2022 . We hypoA 79-year-old male with an unremarkable past medical history and completed lifetime health screenings had his first dose of the mRNA-1273 COVID-19 vaccine on May 12, 2021. Three days later, he developed some pain with swelling in his right lower extremity (RLE) below the knee. He was seen by his primary care physician who ordered a duplex venous ultrasound of the lower extremities; however, it was delayed because of scheduling problems. Meanwhile, he proceeded to receive his 2nd dose of the mRNA-1273 COVID vaccine 28 days after the 1st vaccine dose on June 9, 2021. Worsening of his RLE pain and increased shortness of breath led him to complete the venous doppler ultrasound on June 10, 2021, where an extensive DVT was found along the RLE Figures .The patient subsequently presented to our emergency department (ED). His first set of vital signs upon arrival recorded as blood pressure of 187/83 with a heart rate (HR) of 85 beats per minute, he was afebrile but hypoxic to 87% on room air requiring supplemental oxygen. He was tested for COVID-19 infection with reverse transcription-polymerase chain reaction (RT-PCR) which was negative. Shortly after presentation, he developed atrial fibrillation with rapid response rate, HR reaching 142 before being controlled with beta-blockers. His right leg below the knee was erythematous, warm, and swollen with mild tenderness and intact distal pulse. He denied using tobacco products, alcohol, or illicit substances. He works as a construction worker occasionally and maintains an active lifestyle. He denied history of recent trauma, surgery or prolonged hospitalization, uninterrupted long-distance traveling, or a personal or family history of blood clots.An emergent computed tomography angiography (CTA) of the chest revealed an acute subsegmental right lower lobe pulmonary embolism. Echocardiogram revealed normal ejection fraction without right ventricular strain or structural abnormalities. Troponin was normal at 0.004 ng/ml. His hematologic, metabolic, electrolyte, and coagulation panels were within standard limits except for D-dimer which was elevated to 1.22 ug/ml . He was immediately anticoagulated with intravenous heparin and admitted to a closely monitored unit. Due to persisting hypoxia, he required supplemental oxygen on discharge. Apixaban was chosen for ambulatory anticoagulation, initial dose was 10 mg twice daily for two weeks to be followed by 5 mg twice daily for three months and was advised to follow-up with his primary care physician and pulmonologist.mRNA vaccines are revolutionary gene-based vaccines that instruct the host cells to express spike proteins that closely mimic the natural COVID-19 proteins, triggering an immune response and development of immunity. In December 2020, BNT162b2 and mRNA-1273 were granted emergency use authorization by the US Food and Drug Administration. The reactogenicity of these vaccines, such as fatigue, headache, myalgias, are more common, while their systemic reactions are exceedingly rare, including anaphylaxis . We repoIn a recent post-vaccination database, there were 213 cases of cerebral venous thrombosis - 88% were attributed to ChAdOx1, 12% to BNT162b2, and one case by mRNA-1273 . AnotherScientists are widely discussing vaccine-induced thrombotic thrombocytopenia (VITT) and its role in the multiple incidents of thrombosis following COVID-19 vaccination . In addiAlthough it may be argued that in our patient PF4 antibodies were not checked to evaluate for VITT, the patient tested negative for COVID-19 infection, and he had no other predisposing risk factors for developing acute venous thrombosis. He was generally active, working in the construction industry and using the gym three times a week; therefore, the development of lone DVT and pulmonary embolism due to the mRNA-1273 vaccine is the most plausible explanation. Also causes of clots other than VITT, with a predilection for the venous circuit after receiving mRNA vaccines were reported before. Researchers reported cases of venous thrombosis following COVID-19 vaccine administration with normal platelet counts and negative PF4 antibodies supporting our theory that VITT is not the only reason for VTE following vaccination against COVID-19 .Scientists have discussed the similarity between COVID-19 virus and COVID-19 vaccines . As the Multiple well-known risk factors can lead to VTE. Examples are recent trauma to the leg, recent surgeries, family history of thrombosis, and prolonged immobility. Our patient did not have any of these risk factors. About 40% of the DVT in the general population can be idiopathic in origin . The patAlthough some reports suggest an association between COVID-19 vaccines with the development of VTE, we still recommend COVID-19 vaccination. The risk of developing VTE from the vaccine is significantly lower than the VTE correlated to the actual COVID-19 infection; the hypercoagulable effects of COVID-19 are well established in the literature. Future studies and robust database monitoring can help elicit the true incidence of COVID-19 vaccine-induced thrombosis as more adverse reporting data is collected.


Background and Objectives: Preventive, adjunctive and curative properties of lactoferrin have been evaluated since the first wave of severe acute respiratory syndrome coronavirus (SARS-CoV), a viral respiratory disease, emerged 18 years ago. Despite the discovery of new vaccine candidates, there is currently no widely approved treatment for SARS-CoV-2 (COVID-19). Strict adherence to infection prevention and control procedures, as well as vaccines, can, however, prevent the spread of SARS-CoV-2. This study aimed to evaluate the efficacy of lactoferrin treatment in improving clinical symptoms and laboratory indices among individuals with mild to moderate coronavirus disease-19 (COVID-19). Materials and Method: A randomized, prospective, interventional pilot study conducted between 8 July and 18 September 2020 used a hospital-based sample of 54 laboratory-confirmed participants with mild to moderate symptoms of COVID-19. Randomization into a control and two treatment groups ensured all groups received the approved Egyptian COVID-19 management protocol; only treatment group participants received lactoferrin at different doses for seven days. Clinical symptoms and laboratory indices were assessed on Days 0, 2 and 7 after starting treatments. Mean values with standard deviation and one-way analysis of variance with least significant difference of demographic and laboratory data between control and treatment groups were calculated. Results: Our study showed no statistically significant difference among studied groups regarding recovery of symptoms or laboratory improvement. Conclusions: Further research into therapeutic properties particularly related to dosage, duration and follow-up after treatment with lactoferrin in individuals with COVID-19 is required. The novel severe acute respiratory syndrome coronavirus SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), was first discovered in Wuhan, China in December 2019. It causes a viral pneumonia which may progress to acute respiratory distress and death , the cau,4,5.There is a wide scope of naturally occurring substances, for example, lactoferrin (Lf), that might be formed into expected drugs for treating COVID-19 ,7. LactoLf has been shown to have a wide range of beneficial characteristics. Lactoferrin is found in substantial concentrations in neutrophils and serves as a preventive and pathogen-reduction agent in vitro and in vivo ,14,15. LLactoferrin has been found to have an anti-inflammatory effect on humans . FurtherThis is a randomized, prospective, interventional pilot study using a hospital-based sample of 54 laboratory-confirmed (SARS-CoV-2 positive) participants with mild to moderate symptoms of COVID-19. Recruitment was carried out in the Department of Medicine at Al-Ahrar Hospital, Zagazig, Egypt from 8 July to 18 September 2020. Diagnosis was confirmed by a positive result of reverse transcriptase polymerase detection from a nasopharyngeal swab as indicated in the WHO guidelines .Asymptomatic infection is defined as patients who test positive for SARS-CoV-2 on a virologic test but do not develop COVID-19 symptoms, mild illness is defined as individuals who have COVID-19 symptoms but no evidence of viral pneumonia or hypoxia, moderate illness is defined as people who show clinical symptoms of pneumonia but not severe pneumonia, such as a SpO2 of less than 90% on room air, severe illness is defined as people who express clinical symptoms of pneumonia as well as one or more of the following: a respiratory rate of more than 30 breaths per minute, severe respiratory distress, or a SpO2 of less than 90% on room air and critical illness is defined as individuals who have acute respiratory distress syndrome (ARDS), septic shock and/or multiple organ dysfunction.The definition of mild to moderate COVID-19 was based on interim guidance from the WHO, 2020 . COVID-12) >93%. Exclusion criteria included pregnant and breastfeeding women, individuals confirmed to be allergic to milk protein, those with a medical history of bronchial hyperactivity or pre-existing respiratory diseases and ICU inpatients with COVID-19.Eligibility criteria for inclusion in this study were participants over 20 years of age, positive for nasopharyngeal swab reverse transcriptase polymerase chain reaction (RT-PCR) for COVID-19 and blood oxygen saturation  scans were gathered. In addition, all eligible participants underwent further laboratory tests comprising: complete blood count, liver and kidney function chemistry panels, coagulation profile, C-reactive protein, ferritin and lactate dehydrogenase (LDH) serum levels.The blood samples of all eligible COVID-19-positive participants, body temperature and reported signs and symptoms were collected at Day 0, Day 2 and Day 7. Day 0 represents the first day of starting treatment and blood collection. Day 2 represents the second day of collecting samples after 48 h of starting treatment. Day 7 represents the third day of collecting samples after seven days of starting treatment.Although the recruitment of eligible participants into the study was implemented using a convenience sampling method with a tendency to introduce various ingroup differences, this was minimized by randomization of participants into control group and treatment groups (Group I and II). The randomization process was double blinded wherein the investigators and study participants were not aware of individuals assigned to either the control or treatment groups.2) ≥90%; (b) oral hydroxychloroquine 400 mg two times a day during the first day and 200 mg twice daily for the next 6 days; (c) oral vitamin C 1 g daily; (d) oral zinc 600 mcg daily; (e) oral acetylcysteine 200 mg three times daily.According to Egypt’s approved COVID-19 patient management protocol , all eliThe eligible participants receiving standard protocol treatment were randomly assigned (as described above) into three groups. The first group was the Control Group; participants in the second group were designated as Group I; and participants in the third group were designated as Group II. Each group was made up of 18 participants. None of the participants in the Control Group received lactoferrin. Each participant in Group I received 200 mg lactoferrin orally once daily. Each participant in Group II received 200 mg lactoferrin orally twice daily. Those patients received lactoferrin sachets . Each sachet contained lactoferrin 100 mg and was prepared by dissolving in half a glass of water or juice before meals . The ratp < 0.05) was used. To determine significant differences for parametric data between Control Group and treatment groups (Group I and II), one-way analysis of variance (ANOVA) was performed. Given the small but equal sample sizes within the control and treatment groups, ANOVA was the preferred test of choice since it is still robust for deviations from normality [p value of less than 5% (p < 0.05) and 95% confidence interval levels were reported. All analyses were carried out using Statistical Package for the Social Sciences version 26 (SPSS v.26) and Graphpad Prism 6.Mean values with standard deviation (SD) of demographic and laboratory data were calculated. Mean was found to accurately represent the center distribution of our data after a test of normality was carried out. In addition, the proportion of each clinical characteristic was reported. For non-parametric data , the chi-square test . In In p > 0.05).A pilot study of 54 symptomatic participants diagnosed with COVID-19 in Egypt was conducted. Although clinical and laboratory differences were observed between the control and treatment groups, these differences were not statistically significant.Our study showed improvements in COVID-19 symptoms including fever, dry cough, diarrhea, headache, loss of sense of taste and/or smell and tiredness after the seventh day of starting treatment with Lf in all groups, however these changes showed no statistically significant difference among studied groups. These findings can be explained by the established broad-spectrum antiviral, anti-inflammatory and immunomodulatory properties of Lf ,31,32,33In SARS-CoV-2 infection, serum hemoglobin levels, lymphocyte count and platelet count are expected to decline ,35,36, wIn previous studies, liver function tests in individuals with COVID-19 revealed mixed findings: serum albumin levels are reduced; total bilirubin, alanine aminotransferase and aspartate aminotransferase levels are elevated while prothrombin time and partial thromboplastin time are shortened ,40. In oPrior research indicated elevation of serum urea and creatinine levels in individuals with SARS-CoV-2 infection ,42. HoweC-reactive protein, serum ferritin and lactate dehydrogenase levels in persons with COVID-19 were shown in previous studies to be elevated ,45,46. TThis pilot study in not without inherent limitations. Firstly, the limited sample size of hospital-based participants potentially reduced the power to observe expected statistically significant findings. However, we attempted to mitigate this limitation by making extensive use of descriptive statistics and allocating resources to maximize inference for the most important parameters. Secondly, the combination of short duration of treatment, relative lower dose and lack of follow-up after treatment with Lf administered to participants may have potentially impacted the expected results.The preventive, adjunctive and curative properties of lactoferrin have been evaluated since the emergence of the first wave of the severe acute respiratory syndrome (SARS), a viral respiratory disease, 18 years ago. LF supplementation is undoubtedly a promising field for additional research, however the results of this study do not allow for a definitive conclusion about its potential benefits as a support therapy. Further studies with larger samples, as well as longer-term trials to evaluate if viral clearance can be sustained with continuous administration of Lf, are needed to better understand the role of Lf in treating SARS-CoV-2.


Secondary mitral regurgitation (MR) demonstrates dynamic change during exercise. This prospective observational study aimed to compare exercise stress echocardiography (ESE) where handgrip exercise (handgrip-ESE) or semisupine ergometer exercise was performed (ergometer-ESE) for patients with secondary MR.Handgrip-ESE and symptom-limited ergometer-ESE were performed for 53 patients (median age (IQR): 68 (58–78) years; 70% male) on the same day. Baseline global longitudinal strain (GLS) was 9.2% (6.0%–14.0%) and MR volume was 20 (14–26) mL. All-cause death and cardiac hospitalisation were tracked for median 439 (101–507) days.Handgrip-ESE induced slightly but significantly greater degrees of MR increase  than ergometer-ESE, although the changes in other parameters, including GLS , were significantly smaller. Correlations between the two examinations with respect to the changes in the echocardiographic parameters were weak. Kaplan-Meier analyses revealed poor improvement in GLS during ergometer-ESE, but not the change in MR, was associated with adverse events (p=0.0065). No echocardiographic change observed during handgrip-ESE was prognostic. After adjusting for a clinical risk score, GLS changes during ergometer-ESE remained significant in predicting the adverse events  A subgroup analysis in patients with moderate or greater MR at baseline (n=27) showed the same results as in the entire cohort.The physiological and prognostic implications of handgrip-ESE and ergometer-ESE findings significantly differ in patients with left ventricular dysfunction and secondary MR. The type of exercise to be performed in ESE should be carefully selected. Studies have reported that ergometer-exercise stress echocardiography is useful for prognostic assessment in patients with mitral regurgitation. Since ergometer-exercise is often not feasible for elderly and frail patients, doctors sometimes select handgrip exercise as an alternative. However, it has been unknown that handgrip-exercise stress echocardiography is equivalent to ergometer exercise.Our study clearly showed that although handgrip-exercise stress echocardiography induces similar degree of mitral regurgitation increase, its physiological and prognostic meaning is different from what observed in ergometer-exercise stress echocardiography.Our study raises a caution about handgrip-exercise stress echocardiography as an alternative to ergometer exercise.Secondary mitral regurgitation (MR) is a common complication observed in approximately half of patients with heart failure with left ventricular (LV) dysfunction,7–9Exercise stress echocardiography (ESE) for evaluation of valvular heart disease is a well-known examination, which allows real-time evaluation of the dynamic changes in the severity of valvular regurgitation and LV function. Previous studies have reported that quantitative assessment of MR and LV function during ergometer exercise is reproducible and has prognostic significance for primary MR.2; (2) absence of degenerative changes in the mitral leaflet, such as myxomatous change, billowing, prolapse, heavy calcification, infective endocarditis, anomaly and perforation; (3) absence of active ischaemic disease or significant coronary stenosis; and (4) tolerance to at least 25–50 W of ergometer exercise were enrolled.We conducted a prospective single-centre observational study that included patients who underwent ESE in our hospital from October 2015 to December 2016. Consecutive patients with (1) LV ejection fraction (LVEF) <40% and secondary MR. Based on the European Society of Cardiology and European Association for Cardiothoracic Surgery guidelines,All patients underwent laboratory tests for the assessment of the creatinine and B-type natriuretic peptide levels. The Meta-Analysis Global Group In Chronic heart failure (MAGGIC) mortality risk score was calculated, as described previously.Baseline echocardiography was performed in the supine position at rest. Handgrip-ESE was subsequently performed in the supine position. The patients were asked to grip a dynamometer with half their maximum strength for 8 min using either hand, and echocardiographic images were acquired in the last 3 min of the exercise. The dynamometer indicates a real-time grip strength, and dedicated medical staff was observing the grip strength, confirming that the patient was appropriately keeping the grip strength during the exercise. After the handgrip-ESE, a minimal 30 min interval was ensured before the patients underwent symptom-limited ergometer-ESE. The workload was initially 25 W and was then increased by 25 W every 3 min. Echocardiographic images were acquired at the final workload by an experienced sonographer in the last 1–2 min of the test, as described previously.232 or Fisher’s exact tests for the continuous and categorical variables, respectively. Differences between the continuous parameters obtained at peak exercise and the baseline values were compared using paired t-tests; the differences noted between these changes during the two tests were also evaluated. The MR grade was compared using the Wilcoxon signed-rank test with relevelling of the MR grade to ordinal variables . The Pearson’s correlation tests were used to evaluate the relationship of between the changes in the parameters during handgrip-ESE and those during ergometer-ESE. Weighted kappa was used to test the agreement in the MR grade during the two examinations. Moreover, we evaluated the parameters associated with the changes in MR volume and GLS to assess the mechanisms underlying these changes during the two types of exercise using these tests. For survival analysis, the patients were divided according to the median values of the parameters of interest, and the Kaplan-Meier curve analysis, log-rank test and multivariable Cox proportional hazard models were used. As a sensitivity analysis, we repeated all the analyses with a subgroup of patients who had moderate or greater MR.The data are presented as the median (IQR) for the continuous variables and as the frequency (%) for the categorical variables. Group differences were evaluated using the Mann-Whitney U and ΧAll statistical analyses were performed with R V.3.5.2 . A two-tailed p<0.05 indicated statistical significance.This study was completed without patient involvement.After excluding one patient due to images of insufficient quality, 106 stress tests were performed for 53 patients whose image quality was sufficient for quantitative analysis. The exercise was standardised and submaximal for all. All patients underwent handgrip-ESE and ergometer-ESE without any complications. None of the patients developed any symptoms of ischaemia, such as chest pain, induced wall motion abnormality or ECG changes. The median workload during ergometer-ESE was 50 (50–50) W. The significant increase in heart rate  and blood pressure  by the exercises indicates that the exercises were properly performed, and the amount of workload was significant. MR volume assessment was feasible for all patients, except for one patient due to insufficient image quality for GLS analysis during ergometer-ESE. The assessment of the tricuspid valve regurgitation peak velocity was not feasible for seven patients due to minimum regurgitation, and these patients were excluded from analyses using PAP.10.1136/openhrt-2021-001583.supp1Supplementary dataDuring the median follow-up period of median 439 (101–507) days, 28 patients experienced adverse cardiac events, including deaths of seven patients. The Kaplan-Meier curves, with cut-off values of median values as mentioned above, are shown in Since the degree of baseline MR may impact the results, we performed a sensitivity analysis in patients with moderate or greater MR at baseline (n=27). As summarised in This study reported the first direct comparison between two different types of exercise for ESE for patients with heart failure and secondary MR. The results showed that (1) with appropriate amount of exercise indicated by the changes in vital signs, MR was increased slightly but significantly greater during handgrip-ESE than ergometer-ESE, while other parameters were changed by less degrees during handgrip-ESE than during ergometer-ESE; (2) the correlation between the changes in the parameters during the two examinations was moderate at most, and factors associated with these changes differed between handgrip-ESE and ergometer-ESE, suggesting different underlying physiological changes during the two examinations; and (3) GLS improvement during ergometer-ESE, but not the change in MR, was associated with better clinical prognosis, while none of the echocardiographic changes observed during handgrip-ESE was prognostic, as summarised in The dynamic nature of secondary MR in various conditions is well known. Studies have reported that different kinds of stress conditions lead to different alterations in secondary MR:, such that increase in preload and afterload during the acute phase of heart failure commonly increases secondary MR,et al reported that the changes in the degree of secondary MR during ergometer exercise did not have prognostic implications for patients with severe LV dysfunction and mild-to-moderate MR.Although previous studies have reported the prognostic significance of the deterioration in MR, elevated PAP and lack of LV systolic function in primary MR,The conflicting results from the recent COAPT and MITRA-FR trials have prompted an important discussion regarding the candidates appropriate for non-pharmacological intervention for secondary MR.Our study has several limitations. First, this was a single-centre study including a relatively small number of patients. Thus, the present results, especially the part regarding the clinical outcomes, should be considered as a hypothesis-generating pilot study. Further studies are warranted to confirm our findings. Next, treadmill exercise, one of the most popular types of ESE, was not tested in this study. However, since very quick echocardiographic scanning is required in treadmill ESE, it may not pragmatically be a good choice for valvular heart disease assessment. Another concern is that handgrip exercise tends to be insufficient especially in frail patients. However, in the present study, dedicated medical staff was observing the grip strength, confirming that the patient was appropriately keeping the grip strength during the exercise. In addition, the significant increase in MR during handgrip-ESE indicates that the strength of the exercise was substantial. Last, our study population included a substantial number of patients with mild secondary MR. Nevertheless, the subgroup analysis excluding patients with mild MR showed the same results as in the entire cohort. In addition, the importance of ESE only for patients with severe secondary MR at baseline is limited because most such patients are already symptomatic and do not require further stress tests for evaluation.Handgrip-ESE and ergometer-ESE have significantly different physiological and prognostic implications for patients with LV dysfunction and secondary MR. The pattern of cardiac haemodynamic changes during both types of ESE was different, and only improvement in the GLS during ergometer-ESE was associated with adverse events. These results suggest that handgrip-ESE may not be appropriate for risk assessment of patients with secondary MR, although handgrip-ESE is easier to perform. The type of exercise to be performed during ESE should be carefully selected.


Data regarding the prevalence of mesenteric artery stenosis in patients undergoing transcatheter aortic valve implantation (TAVI) are scarce. Whether patients with high-risk features for acute mesenteric ischemia (AMesI) have a worse prognosis compared with those without high-risk features is unknown. We aimed to address these questions.We included 361 patients who underwent TAVI between 2015 and 2019. Using pre-TAVI computed tomography exams, the number of stenosed arteries in each patient and the degree of stenosis for the coeliac trunk (CTr), SMA and inferior mesenteric artery (IMA) were analyzed. High-risk features for AMesI were defined as the presence of ≥2 arteries presenting with ≥50% stenosis. Patient demographic and echocardiographic data were collected. Endpoints included 30-day all-cause mortality, mortality and morbidity related to mesenteric ischemia.p < 0.001) and higher mortality related to AMesI , compared with non-high-risk patients.22.7% of patients had no arterial stenosis, while 59.3% had 1 or 2 stenosed arteries, and 18.0% presented stenoses in 3 arteries. Prevalence of significant stenosis (≥50%) in CTr, SMA, and IMA were respectively 11.9, 5.5, 10.8%. Twenty patients at high-risk for AMesI were identified: they had significantly higher all-cause mortality (15.0 vs. 1.2%, Patients at high-risk for AMesI presented with significantly higher 30-day all-cause mortality and mortality related to AMesI following TAVI. Mesenteric revascularization before TAVI interventions may be beneficial in these patients. Prospective studies are needed to clarify these questions. Mesenteric artery stenosis (MAS) is a frequent incidental finding on abdominal imaging, with more than 90% of cases believed to be of atherosclerotic origin . The indFrom January 1st 2015 to December 31st 2019, all patients who underwent TAVI interventions in our institution , with available pre-intervention CT imaging data, were included. The CHUV serves as an academic tertiary-care hospital for a major part of the French-speaking population of Switzerland.Commission cantonale d'éthique de la recherche sur l'être humain), decision CER-VD 211/13, dated May 10th, 2013.All patients belonged to the SWISS TAVI Registry and provided written informed consent for the use of their data for research purposes. The study was conducted in accordance with the Declaration of Helsinki. Ethical approval was given by the local ethics commission , with patients lying on their back, arms raised above their head, in a single breath-hold. Cardiac ECG-gated non-contrast images were first acquired to compute the aortic valve calcium score . In a second step, ECG-gated CT angiography of the carotid arteries, aorta, and iliac arteries was performed in the craniocaudal direction, following 100 mL of 350 mg/mL of iodinated contrast medium  injected into an antecubital vein (on the right side whenever possible). Images were analyzed by two radiologists, with any disagreement resolved by consensus or with the help of a third senior radiologist. Interrater variability for superior mesenteric artery (SMA) stenosis assessment has been evaluated previously . Data weThe coeliac trunk (CTr), superior mesenteric artery (SMA) and inferior mesenteric artery (IMA) were analyzed in all patients. Each artery was classified according to lumen narrowing expressed in percentage of the reference diameter: normal (0%), mild stenosis (<50%), moderate stenosis (50 to 69%), severe stenosis (70 to 99%), or occlusion (100%). The total number of stenosed arteries 0, 1, 2, or 3) in each patient, regardless of stenosis severity, was also collected. Patients at high-risk for AMesI were defined as those presenting with at least 2 arteries out of 3 presenting each with ≥50% stenosis . Figures, or 3 inBaseline patient demographic characteristics, including gender, age, body mass index (BMI), major comorbidities (such as diabetes mellitus and coronary artery disease), and echocardiographic data (left ventricular ejection fraction [LVEF]) were collected. Post-operative endpoints included 30-day all-cause mortality, 30-day mortality related to AMesI , all cases of AMesI within 30 days after TAVI. Only cases where the diagnosis of AMesI was confirmed based on an abdominal CT exam or perioperatively if the patient directly underwent abdominal surgery, were counted.2 test. Continuous variables were reported as means with standard deviations (SDs) or medians with interquartile ranges (IQRs) and were tested for normality distribution using the Shapiro-Wilk test. Student's t-test was used to compare normally distributed continuous variables, whereas the Mann-Whitney test was used to compare non-normally distributed ones. Thirty-day survival curves were modeled using the Kaplan-Meier method and were analyzed using a log-rank test. Values with a p < 0.05 were considered statistically significant. The SPSS 27.0 software  was used for all statistical analyses.Categorical variables were expressed as frequencies and percentages and compared using Pearson's χA total of 361 patients were included in our study. The distribution of the patients according to the number of stenosed arteries, regardless of stenosis severity, is presented in p = 0.030) and higher prevalence of chronic obstructive pulmonary disease . No significant difference was found regarding the other baseline patient characteristics, although a trend toward lower BMIs and higher prevalence of dyslipidemia was found in high-risk patients.Baseline patient demographic, clinical, and echocardiographic characteristics are presented in p < 0.001) and higher mortality related to AMesI . Among the three patients at high-risk for AMesI who died, one died of AMesI, while two died of extra-digestive causes (acute respiratory failure in both cases). There was a non-significant trend toward a higher incidence of AMesI in high-risk patients . Kaplan-Meier survival curves for 30-day all-cause mortality and mortality related to AMesI are presented in Thirty-day outcomes are presented in Our results can be summarized as follows: (1) among the 361 patients undergoing pre-TAVI routine CT screening, 279 (77.3%) presented with at least one stenosed mesenteric artery and 20 (5.5%) were at high-risk for AMesI, (2) patients at high-risk for AMesI had significantly more comorbidities and higher surgical risk, compared with those not at high-risk, (3) patients at high-risk for AMesI at baseline presented with increased risks of 30-day all-cause mortality and 30-day mortality related to AMesI following TAVI.Routine CT exams performed in patients eligible for TAVI constitute an important database to analyze asymptomatic MAS. This is all the more interesting as available data in the literature on asymptomatic MAS is very scarce. A previous retrospective study compared the prevalence of MAS in 73 patients planned for TAVI interventions who underwent routine CT imaging against 111 control patients who had CT imaging for other reasons . StenoseAlthough an increased risk of all-cause 30-day mortality was observed in patients at high-risk for AMesI compared with those not at high-risk, the two population groups were not comparable, as patients at high-risk for AMesI had a significantly higher surgical risk and more comorbidities. To which extent these differences regarding baseline characteristics have biased our results is unclear. Likewise, it is not possible to conclude if high-risk features for AMesI are mere markers of overall frailty or are independent predictors of mortality. In that sense, considering mortality related to AMesI may be more relevant, as potential confounding factors may less influence this endpoint. Concerning mortality related to AMesI in all our patients, it is worth noting that one previous study analyzing vascular complications in 102 patients undergoing TAVI found five major vascular complications, of which one was AMesI, with a fatal outcome at day 7. This rate of approximately 1% lies in the same range as our data .p < 0.001) and suffered greater in-hospital mortality   to reduce cardiac output and achieve cardiac standstill, thus allowing optimal positioning of the THVs . Rapid vThe number of patients at high-risk for AMesI was relatively low (20 out of 361), yet the risk of 30-day mortality  was significantly increased. In our opinion, this highlights the importance of adequately screening and following these patients. The indication for pre-TAVI mesenteric revascularization should be tailored to each situation, and, in the absence of clear recommendations, it should be discussed on a case-by-case basis. This is all the more important as MAS is now easily treatable in most cases via an endovascular approach . This approach has become the gold standard in most centers in the past decade and may be associated with significantly lower morbidity and mortality compared with open surgical revascularization , 14. AftOur study is subject to some limitations. First, patients at high-risk for AMesI and those not at high-risk for AMesI had significantly different baseline surgical risk and comorbidities; to which extent this may have affected the outcomes of interest is unclear. We tried to overcome this issue by adjusting for differences in comorbidities at baseline, but because of the small sample of patients with high-risk features and the relatively low overall mortality rate, statistical power was insufficient to consider a multivariable analysis. However, despite this limitation, our findings are hypothesis-generating. Secondly, we only compared 30-day outcomes after TAVI, but a more extended analysis period may be interesting. Finally, the results reported here are those of a single Swiss tertiary center and may not be transposable to other populations and centers.To our knowledge, this study is the first report evaluating the prognosis of patients at high-risk for AMesI after TAVI interventions. These patients presented with higher 30-day all-cause mortality and mortality related to AMesI, provided they had more comorbidities and higher surgical risk compared with those not at high-risk for AMesI. Although these results need to be confirmed with larger cohorts, they are hypothesis-generating in so far as mesenteric revascularization before TAVI interventions may be beneficial in patients presenting with high-risk features for AMesI. Further prospective studies are needed to clarify this question.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by CER-VD 211/13. The patients/participants provided their written informed consent to participate in this study.HL: data curation, formal analysis, methodology, and writing . DR, PM, and SQ: supervision, validation, and writing (review and editing). OM, ME, MG, EE, and MK: validation. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The best treatment strategy for oesophageal cancer patients achieving a complete clinical response after neoadjuvant chemoradiation is a burning topic. The available diagnostic tools, such as 18F-FDG PET/CT performed routinely, cannot accurately evaluate the presence or absence of the residual tumour. The emerging field of radiomics may encounter the critical challenge of personalised treatment. Radiomics is based on medical image analysis, executed by extracting information from many image features; it has been shown to provide valuable information for predicting treatment responses in oesophageal cancer. This systematic review with a meta-analysis aims to provide current evidence of 18F-FDG PET-based radiomics in predicting response treatments following neoadjuvant chemoradiotherapy in oesophageal cancer. A comprehensive literature review identified 1160 studies, of which five were finally included in the study. Our findings provided that pooled Area Under the Curve (AUC) of the five selected studies was relatively high at 0.821 (95% CI: 0.737–0.904) and not influenced by the sample size of the studies. Radiomics models exhibited a good performance in predicting pathological complete responses (pCRs). This review further strengthens the great potential of 18F-FDG PET-based radiomics to predict pCRs in oesophageal cancer patients who underwent neoadjuvant chemoradiotherapy. Additionally, our review imparts additional support to prospective studies on 18F-FDG PET radiomics for a tailored treatment strategy of oesophageal cancer patients. https://www.crd.york.ac.uk/prospero/, identifier CRD42021274636. Globally, oesophageal carcinoma is the seventh most frequently diagnosed cancer and sixth leading cause of cancer-related death . In 2020Despite the survival benefits of this combined approach, oesophagectomy is considered a highly invasive procedure with a significant rate of morbidity and mortality, potentially affecting long-term quality of life. Consequently, the active surveillance strategy in case of clinical complete response (cCR) following chemoradiotherapy is a debatable topic –7. This On the other hand, persistent disease after chemoradiotherapy is usually associated with poorer long-term prognosis, which may suggest more aggressive and resistant tumour biology requiring an immediate and aggressive surgical approach. The early identification of tumours not responding to chemoradiotherapy is clearly another significant area for future investigation on the optimal timing of the treatment sequence.Endoscopy/endoscopic ultrasound and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) are the current diagnostic tools for baseline staging as well as the evaluation of treatment responses. Although endoscopy and ultrasound have an accuracy assessment of around 70%, and 18-FDG PET/CT identified a complete response in 71–88% of cases, no current procedure can accurately predict the treatment response ) to arrive at a comprehensive quantification of tumour phenotypes for the prediction of the treatment response and outcome . This emPreliminary data for oesophageal and gastro-oesophageal cancer suggest a potential for radiomics approaches in improving patient stratification for therapy .To date, the published studies are based on several radiologic images  and systematic reviews and meta-analysis based their conclusions on radiomics findings of both morphologic and metabolic diagnostic images .18F-FDG PET-based radiomics seems promising for the management of oesophageal cancer patients concerning the prediction of the treatment response in addition to orienting tailored treatments . HoweverPreferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were employed in conducting this study . The metA comprehensive search strategy, used on PubMed, Scopus, Web of Science, and EMBASE to identify all relevant studies irrespective of language or publication status, was performed until 15 November 2021. Duplicates were manually removed. After a comprehensive selection process, the reference lists of all the identified studies were checked.The search strategy was  AND (cancer OR neoplasia) AND (radiomics OR radiomics features OR radiomic) AND (response OR remission OR outcome OR prognostic OR predictive OR predicting OR prediction)Studies were included if they strictly met the following criteria: 1) Patients with oesophageal and gastro-oesophageal cancer who had received neoadjuvant chemoradiation; 2) 18F-FDG PET/CT imaging was performed; 3) Radiomics was used to predict a pCR; 4) Area Under the Curve (AUC) was determined; 5) Any models/algorithm applied to predict the pathological response.Studies that did not report results in AUC, accuracy, sensitivity, and specificity, lacked proof of validation, or had insufficient detail regarding algorithm development and extraction of diagnostic accuracy were excluded.Two reviewers independently screened the identified articles based on their titles and abstracts (LD and SDD), which were considered in constructing a list of all potentially relevant papers. The full-text versions of potentially eligible studies were assessed against the eligibility criteria. The authors planned to solve disagreements concerning study selection or quality assessment by consensus or discussion with a third member of the review team (AV) and reported this in the final review. However, no disagreement was present, and consequently, the kappa statistic was not determined.The primary endpoint was set as the highest AUC in the validation set (training set). When external validation was not present, we chose internal validation results. If the internal validation was not reported, the result from the training set was chosen. In the absence of the AUC, the C-index was used.Two authors (LD and SDD) independently extracted the following information:General study characteristics Study population (source of data and sample size)Clinical outcomes Treatment scheduleAlgorithm used for the outcome predictionDimensionality reduction methodsResults: highest AUC and standard errorIf the standard error was not indicated, we determined it through Hanley and McNeil’s formula . On the Two authors (LD and SDD) assessed the study quality through the Radiomics Quality Score (RQS) , rangingThe researchers planned to assess the risk of bias using a funnel plot, however, as the number of studies was lower than 10, we did not report this following the Cochrane Handbook .2 scores are divided into the following: moderate heterogeneity (30–60%), substantial heterogeneity (50–90%), or considerable heterogeneity (75–100%). The meta-analysis was executed by MedCalc Statistical Software version 19.2.6 .After extracting the highest AUC and Standard Error, the random-effects model was used to calculate the pooled AUC. Heterogeneity was assessed using the Cochrane Q-test and I² statistic, where a p-value < 0.05 indicated statistically significant heterogeneity. Accordingly, IA flow diagram of the search strategy results is presented in Radiomics Quality Score (RQS) for each of the five included studies is reported in According to the International Symposium on Biomedical Imaging (ISBI) standards, the radiomics features are divided into morphology class , first-order class , and second-order class .One study used the morphology class feature  while thFour out of five studies used features selection methods for dimensionality reduction –22, whilAmong studies that adopted features selection methods, three adopted wrapper methods –22. In pThe authors provided a descriptive summary of the characteristics of the studies in We included a total of five studies: three carried out in the USA , 21, 23,One study included more than 200 patients –24.Altogether, 534 patients were included in this study . The patients’ median age ranged between 35 years  and moreAll patients were treated with external beam radiation therapy and concurrent chemotherapy. A total radiation dose ranging from 40 to 50.4 Gy was delivered in daily fractions of 1.8–2Gy. Among the 534 patients analysed in the 5 studies, in the vast majority of cases RT was delivered with three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) –22, in a2 was 96.46% (95% CI: 94.00–97.92%) , displaying a substantial heterogeneity among studies. After excluding the small studies , AUC was 0.829 (95% CI: 0.719–0.938) (The pooled AUC for the five studies was 0.821 (95% CI: 0.737–0.904), according to the results from To the best of our knowledge, this is the first meta-analysis exclusively analysing the power of 18F-FDG PET-based radiomics to predict the pCR after neoadjuvant chemoradiotherapy in oesophageal and gastro-oesophageal junction cancer.In oesophageal cancer, 18F-FDG PET/CT is part of the initial work-up improving the accuracy of the clinical staging and better assessing distant metastatic disease and is frequently incorporated into radiotherapy planning . MoreoveRadiomics is an advanced method to extract imaging features and thereby quantify tumour phenotype from medical images . Using rAmong them, texture analyses depicting and objectively quantifying tumour heterogeneity seem to be of great interest in order to identify potentially responders and non-responders , 18. Morvs T3) and negative post-treatment endoscopic biopsy significantly influence the probability of pCR . Thus, substantial heterogeneity existed among the studies: this is explained by different image scanners and imaging elaboration, which influenced radiomics features  and not influenced by the studies’ sample size. Moreover, the Ifeatures .The dissected studies’ RQS ranged from 5  to 16 2 – considOverall, none of the analysed studies performed a cost-effectiveness analysis; they were not prospective, did not perform a phantom study or imaging at multiple time points, or had a biological correlation. Similarly, in a recent systematic review on nasopharyngeal tumours using MRI radiomics features, none of the included studies executed neither a phantom study nor a cost-effectiveness analysis . ConversIn the future, the RQS principles should be considered before planning radiomics studies to ensure satisfactory quality. Although a high- or low-quality range was not stated in the RQS guidelines , a cut-ovs. squamous cell cancer) could not be performed in the present meta-analysis.Among the five studies included in our analysis, three enrolled a majority of adenocarcinoma 335/368 –22, whilNeoadjuvant chemoradiotherapy followed by surgery is a well-established approach in oesophageal squamous cell carcinoma and gastro-oesophageal adenocarcinoma , 31, whiThe articles included in this review suggest that first- and second-order features contributed to the response assessment, predominantly in predicting pCR. Tumours with low heterogeneity were more likely to reach a pCR. In detail, van Rossum et al. developed a prediction model adding four comprehensive 18F-FDG PET texture/geometry features  and improved the AUC to 0.77 instead of the 0.67 obtained with clinical models . A tumouMore recently, Murakami et al. constructed a predictive model with a good AUC score of 0.95, extracting 22 second-order radiomics features . Lastly,As reported in literature and in our findings, tumour heterogeneity seems to have impact on tumour response, since tumours with greater intratumoral heterogeneity are often assumed to have an aggressive biology . HoweverOverall, radiomics features could objectively and quantitatively describe distinctive tumour “radio-phenotypes”. In future, all these radio-phenotypes could potentially substitute a “real biopsy” and explain treatment sensibility or resistance describing and identifying metabolic activity, proliferation grade, angiogenesis as well as genomic stability or instability .Remarkably, we discovered that the pooled AUC after excluding two small studies with less than 70 patients remains pretty high at 0.829 (95% CI: 0.719–0.938). A recent review underlined the relevance of the sample size to allow high dimensional models and machine learning approaches to be statistically robust considering an adequate cut-off > 100 or > 200 patients. The performance of the existing algorithm would be applied to new large datasets . In the A machine-learning algorithm was used in four out of the five studies , 22–24. Despite the encouraging findings of the present meta-analysis in using 18F-FDG PET/CT radiomics to predict treatment responses in oesophageal cancer, some limits should be underlined. First, few studies were included; thus, publication bias analysis was not performed because it was not appropriate. Second, all included studies were retrospective and performed in a monocentric setting. Third, demographic heterogeneities were observed among studies due to different race ethnicity. Furthermore, they used different PET scanners, and the selection of the features was based on different methodologies, distinct methods of tumour volume segmentation , and often on differing in-house software. An additional limitation of these studies is that their authors focused on different feature sets, and the data analysis and interpretation were based on several approaches. Moreover, only one study  reportedBased on these results, we conclude that 18F-FDG PET/CT-based radiomics images have a high accuracy in predicting pCR to neoadjuvant chemoradiotherapy. Overall, the main concern is reaching higher data quality in oesophageal and gastro-oesophageal junction cancer. Next step is to plan studies incorporating quality control. Future research should focus on developing predictive models, through well-designed and appropriately powered prospective studies, with the aim to complement the current clinical findings with radiomics, and further stratify and personalise oncologic treatment.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.LD, MG, and SD contributed to conception and design of the study. MG performed the statistical analysis. LD and MG wrote the first draft of the manuscript. SD and AV wrote the discussion. GP and SC helped collect literature and participated in discussions. DL, MV, DLR, MC, and MCP examined and verified the results. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Is nivolumab-ipilimumab combination therapy cost-effective as first-line treatment for patients with advanced non–small cell lung cancer compared with platinum-doublet chemotherapy?In this economic evaluation of the cost-effectiveness of nivolumab-ipilimumab combination therapy, a Markov model was designed to simulate patients with advanced non–small cell lung cancer who were receiving either nivolumab-ipilimumab combination therapy or platinum-doublet chemotherapy. In this model, nivolumab-ipilimumab combination therapy was not found to be cost-effective at a willingness-to-pay threshold of $100 000 per quality-adjusted life-year, with an incremental cost-effectiveness ratio of $401 700 per quality-adjusted life-year compared with chemotherapy.The findings suggest that first-line treatment with nivolumab-ipilimumab combination therapy is not cost-effective at current prices despite clinical trial data indicating that this therapy increases overall survival among patients with advanced non–small cell lung cancer. Treatment with nivolumab-ipilimumab combination therapy was found to improve overall survival compared with chemotherapy among patients with advanced non–small cell lung cancer (NSCLC) in the CheckMate 227 clinical trial. However, these drugs are substantially more expensive than chemotherapy and, given the high incidence of advanced NSCLC, the incorporation of dual immune checkpoint inhibitors into the standard of care could have substantial economic consequences.To assess whether nivolumab-ipilimumab combination therapy is a cost-effective first-line treatment for patients with advanced NSCLC.This economic evaluation designed a Markov model to compare the cost-effectiveness of nivolumab-ipilimumab combination therapy with platinum-doublet chemotherapy as first-line treatment for patients with advanced NSCLC. The Markov model was created to simulate patients with advanced NSCLC who were receiving either nivolumab-ipilimumab combination therapy or platinum-doublet chemotherapy. Transition probabilities, including disease progression, survival, and treatment toxic effects, were derived using data from the CheckMate 227 clinical trial. Costs and health utilities were obtained from published literature. Data analyses were conducted from November 2019 to September 2020.Nivolumab-ipilimumab combination therapy.The primary study outcomes were quality-adjusted life-years (QALYs) and cost in 2020 US dollars. Cost-effectiveness was measured using an incremental cost-effectiveness ratio (ICER), with an ICER less than $100 000 per QALY considered cost-effective. Model uncertainty was assessed with 1-way and probabilistic sensitivity analyses.Treatment with nivolumab-ipilimumab combination therapy was associated with an increase in overall cost of $201 900 and improved effectiveness of 0.50 QALYs compared with chemotherapy, yielding an ICER of $401 700 per QALY. The study model was sensitive to the cost and duration of immunotherapy. Treatment with nivolumab-ipilimumab combination therapy became cost-effective when monthly treatment costs were reduced from $26 425 to $5058 (80.9% reduction) or when the maximum duration of immunotherapy was reduced from 24.0 months to 1.4 months. The model was not sensitive to assumptions about survival or programmed cell death 1 ligand 1 status. A probabilistic sensitivity analysis indicated that, at a willingness-to-pay threshold of $100 000 per QALY, nivolumab-ipilimumab combination therapy was less cost-effective than chemotherapy 99.9% of the time.In this study, first-line treatment with nivolumab-ipilimumab combination therapy was not found to be cost-effective at current prices despite clinical trial data indicating that this regimen increases overall survival among patients with advanced NSCLC. This economic evaluation uses data from the CheckMate 227 clinical trial and a Markov model to examine the cost-effectiveness of nivolumab-ipilimumab combination therapy vs platinum-doublet chemotherapy as first-line treatment for patients with advanced non–small cell lung cancer. Approximately one-half of patients with NSCLC present with advanced or metastatic disease,3 and a substantial proportion of patients with local or locoregional disease subsequently develop recurrent or metastatic disease.6 Among those with distant disease, the prognosis remains poor, with 5-year relative survival rates of approximately 5%.7 Given these data, new treatments for this disease are needed.Lung cancer represents the second most common type of cancer and the leading cause of cancer-related death in the US,8 The ongoing CheckMate 227  clinical trial recently found that the combination of 2 immune checkpoint inhibitors, nivolumab and ipilimumab, as first-line treatment improved overall survival in patients with advanced NSCLC compared with platinum-doublet chemotherapy, independent of a tumor’s programmed cell death 1 ligand 1 (PD-L1) expression level.9 Treatment with nivolumab-ipilimumab combination therapy also improved progression-free survival and had lower rates of adverse events compared with chemotherapy. The clinical trial also included patients who received treatment with nivolumab with or without chemotherapy (depending on PD-L1 expression level) and found nivolumab-ipilimumab combination therapy to be more efficacious than nivolumab monotherapy. In addition, nivolumab-ipilimumab combination therapy resulted in fewer adverse events than nivolumab with chemotherapy but more adverse events than nivolumab without chemotherapy. Overall, these results led to consensus guidelines listing nivolumab-ipilimumab combination therapy as a first-line treatment option for select patients with metastatic NSCLC.8The treatment options for patients with advanced NSCLC have expanded substantially in recent years. Newer therapies, such as immune checkpoint inhibitors, have increasingly become part of the standard of care for this disease.13 Aside from the direct consequences for patients, advanced NSCLC has a high incidence rate, and the widespread adoption of costly drugs could add to the increasing costs of cancer care in general. These economic health care concerns suggest that assessment of the value or cost-effectiveness of these drugs is needed. In this study, we aimed to evaluate the cost-effectiveness of nivolumab-ipilimumab combination therapy compared with chemotherapy as first-line treatment for patients with advanced NSCLC.Despite the efficacy of nivolumab-ipilimumab combination therapy for the treatment of advanced NSCLC, one must consider the high costs of these agents. These high costs can have consequences for patients in the form of financial toxicity, leading patients to forgo or delay care, decreasing quality of life, and putting patients at risk of bankruptcy.14 including the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guideline for economic evaluations. This study included published clinical trial data without individual patient data and was therefore deemed exempt from review by the institutional review board of the University of California, San Diego.This economic evaluation followed standard guidelines for the design, analysis, and reporting of our model,9 In our model, patients could progress through 4 main health states: stable disease, stable disease during receipt of second-line treatment, disease progression, and death. We constructed a Markov model to simulate costs, quality of life, toxic effects, progression, and survival among patients receiving nivolumab-ipilimumab combination therapy or chemotherapy as first-line treatment for advanced NSCLC. We built our model and derived model inputs based on results reported in the CheckMate 227 clinical trial.17 we sought to assess the cost-effectiveness of dual checkpoint inhibition with nivolumab-ipilimumab combination therapy compared with chemotherapy. Our primary cost-effectiveness analysis used all patient data from the CheckMate 227 clinical trial (regardless of PD-L1 status). Sensitivity analyses were performed to evaluate cost-effectiveness within the PD-L1 groups (<1% and ≥1%) separately. We also evaluated cost-effectiveness among patients with PD-L1 levels of 50% or higher in a separate sensitivity analysis.The CheckMate 227 clinical trial stratified patients by PD-L1 expression level (≥1% or <1%) and randomized patients to receive chemotherapy alone, nivolumab therapy with or without chemotherapy (depending on PD-L1 level), or nivolumab-ipilimumab combination therapy. Given that the cost-effectiveness of mono–checkpoint inhibition among patients with advanced NSCLC has been evaluated elsewhere,Our base case model followed the CheckMate 227 trial protocol, in which patients received treatment with nivolumab-ipilimumab combination therapy until disease progression, development of unacceptable toxic effects, or 2 years of treatment time, whichever occurred first. Per the CheckMate 227 protocol, certain patients could continue receiving immunotherapy after disease progression if they met prespecified criteria; therefore, we conducted a sensitivity analysis in which patients who experienced disease progression continued to receive immunotherapy for up to 2 years regardless of disease progression. In accordance with the Checkmate 227 protocol, patients who were receiving upfront chemotherapy in our base case model also received treatment until disease progression, development of unacceptable toxic effects, or 3 months (4 chemotherapy cycles) of treatment time, whichever occurred first. In addition, per the CheckMate 227 protocol, patients with nonsquamous histologic characteristics could optionally receive maintenance pemetrexed chemotherapy until disease progression or unacceptable toxic effects. The proportion of patients in the CheckMate 227 clinical trial who received maintenance pemetrexed was not published. Therefore, our base case model did not include maintenance pemetrexed; however, we performed a separate sensitivity analysis in which all patients with nonsquamous histologic characteristics received maintenance pemetrexed. In all treatment arms, we assumed that patients who discontinued first-line treatment transitioned to a second-line systemic treatment (37.7% of patients in the nivolumab-ipilimumab therapy arm and 53.7% of patients in the chemotherapy arm), as reported by the CheckMate 227 clinical trial.20 we included and evaluated only grades 3 to 5 treatment-related adverse events. Progression and survival data were extracted from the reported Kaplan-Meier curves using previously described methods.22 Model validation is shown in 23 We tested a second scenario using a sensitivity analysis in which we assumed all patients who were alive after 42 months were cured of their cancer and followed the age-adjusted survival probabilities of the general US population provided by actuarial life tables from the US Social Security Administration.24Patients entered the Markov model in the stable disease state; they could then remain in the stable disease state or experience toxic effects, disease progression, or death. The transition probabilities for these events were derived from CheckMate 227 data. Similar to previous cost-effectiveness studies,30 with a 7% reduction22 plus with the costs of infusion19 and follow-up and monitoring.31 Details regarding the ways in which drug costs were estimated are available in the eMethods in the 32 transportation,33 and caregiver34 costs) and non–health care sector costs (productivity loss32). All costs were adjusted to 2020 US dollars using the Consumer Price Index35 and are shown in the 44We considered costs from both a health care  and societal perspective. Drug costs were calculated by summing the drug’s average wholesale price14; specific values in this study were obtained from published literature. Experiencing toxic effects was considered a decrement in health utility (otherwise known as a disutility) that extended over a 1-month period. Similar to toxic effects costs, we calculated weighted averages for the disutility associated with specific toxic effect events that paralleled the frequency of events in the CheckMate 227 clinical trial , which is a weighted aggregate of health utilities over time. Health utility is measured on a scale of 0 to 1, with 1 corresponding to optimal health and 0 corresponding to death45 with ICERs less than $100 000 per QALY considered cost-effective.46 The ICERs were rounded to the nearest $100. We performed 1-way deterministic sensitivity analyses of each variable in the model to evaluate which variables had the greatest consequences for cost-effectiveness. To further assess model uncertainty, we performed a probabilistic sensitivity analysis using a Monte Carlo simulation with 100 000 repetitions, allowing us to simultaneously vary uncertainty in cost, health utilities, and transition probabilities. In our probabilistic sensitivity analysis, cost variables were modeled with gamma distributions, and health utilities and transition probabilities were modeled with beta distributions. Standard deviations for each distribution were obtained from the literature, when possible. Unknown SDs were calculated using 20% of the mean.47 We also tested a range of possible unknown SDs (10%-40% of the mean), which did not change our results. Data analyses were conducted from November 2019 to September 2020.Cost-effectiveness was measured using an incremental cost-effectiveness ratio (ICER), which is the ratio of the differences in cost (measured in US dollars) and effectiveness (measured in QALYs) between the 2 treatments. We used a willingness-to-pay threshold of $100 000 per QALY,Our base case analysis indicated that nivolumab-ipilimumab combination therapy was associated with a $201 900 increase in the overall cost of treatment from $175 500 for chemotherapy to $377 400 for nivolumab-ipilimumab therapy. Treatment with nivolumab-ipilimumab combination therapy was associated with an increase in effectiveness of 0.50 QALYs from 1.18 QALYs for chemotherapy to 1.68 QALYs for nivolumab-ipilimumab combination therapy. This increase yielded an ICER of $401 700 per QALY, which would not be considered cost-effective at a willingness-to-pay threshold of $100 000 per QALY. Considering cost-effectiveness from a societal perspective yielded an ICER of $434 400 for nivolumab-ipilimumab combination therapy compared with chemotherapy.In the 1-way sensitivity analyses, our model was modestly sensitive to the cost and duration of nivolumab-ipilimumab combination therapy  of 0.73  for the risk of death among patients receiving nivolumab-ipilimumab combination therapy compared with chemotherapy. When we assumed an HR of 0.64 (the lower end of the 95% CI) for the risk of death, the ICER decreased to $249 300 per QALY B. Our baOur model was also not particularly sensitive to PD-L1 expression level. When we incorporated disease progression, survival, and toxic effects data for the cohorts of patients with PD-L1 levels less than 1%, 1% or higher, and 50% or higher, we found ICERs of $332 100 per QALY, $440 100 per QALY, and $375 700 per QALY, respectively. The results of all sensitivity analyses are summarized in eTable 4 in the Probabilistic sensitivity analysis comparing the cost-effectiveness of nivolumab-ipilimumab combination therapy vs chemotherapy found that, at a willingness-to-pay threshold of $100 000 per QALY, chemotherapy would be the cost-effective option 99.9% of the time . When weIn this cost-effectiveness study, we found that nivolumab-ipilimumab combination therapy compared with chemotherapy could not be considered cost-effective as first-line treatment for patients with advanced NSCLC. Our model was not particularly sensitive to assumptions regarding costs, health utilities, or transition probabilities. Of note, the monthly price of nivolumab-ipilimumab combination therapy would have to be reduced from $26 425 to $5058 (an 80.9% reduction) to be cost-effective compared with chemotherapy. In addition, our model found that the maximum duration of treatment with nivolumab-ipilimumab combination therapy would need to decrease to 1.4 months to become cost-effective.48 The CheckMate 153  clinical trial also found that patients with advanced NSCLC who discontinued nivolumab after 1 year had worse progression-free survival compared with patients who received continuous treatment.49 The ongoing DICIPLE  phase 3 clinical trial of patients with advanced NSCLC will further assess the consequences of nivolumab-ipilimumab treatment duration; however, it seems unlikely that the duration required for optimal impact will decrease to the point at which dual checkpoint inhibition would become cost-effective. Of note, our model was not particularly sensitive to assumptions about survival, and cost-effectiveness did not depend on patients’ PD-L1 expression level.The question of immunotherapy duration remains unanswered in oncologic research; however, one study of patients with advanced melanoma found that those who received treatment with pembrolizumab-nivolumab combination therapy for less than 6 months had higher risks of disease progression compared with those who received treatment for more than 6 months.51 The first study50 reported slightly lower ICERs when comparing nivolumab-ipilimumab combination therapy with chemotherapy . The researchers used a higher willingness-to-pay threshold ($150 000 per QALY) and concluded that nivolumab-ipilimumab combination therapy could be considered cost-effective among patients with a PD-L1 level of less than 1%. The second study51 also found slightly lower ICERs when comparing nivolumab-ipilimumab combination therapy with chemotherapy  and used a willingness-to-pay threshold of $150 000 per QALY. In contrast to the first study, researchers in the second study concluded that nivolumab-ipilimumab combination therapy could be considered cost-effective among patients with PD-L1 levels of 50% or higher and 1% or higher but not among patients with PD-L1 levels of less than 1%. Our study found both higher incremental costs and lower incremental effectiveness (as measured by QALY) for nivolumab-ipilimumab combination therapy compared with these other studies, which produced substantially higher ICERs in our analysis.To our knowledge, 2 studies exist on the cost-effectiveness of nivolumab-ipilimumab combination therapy for the treatment of advanced NSCLC.Our methodology differs from the 2 previous cost-effectiveness studies in several areas. First, we used a different approach to model disease progression and survival that used Kaplan-Meier estimates in the CheckMate 227 clinical trial and incorporated long-term poststudy survival estimates from different outside resources. Second, our approach to modeling health utility for stable disease and disease progression differed from those studies. Overall, our model was not particularly sensitive to assumptions about survival or health utilities, which suggests that these factors individually would not account for differences between the results of our study and those of other studies that reported lower ICERs. However, a series of small differences in model construction and variable choice may explain the differences in ICERs between our study and previous research.52 However, for the treatment of advanced melanoma55 and metastatic colorectal cancer,56 nivolumab-ipilimumab combination therapy was not found to be cost-effective compared with a variety of other treatments, including both immunotherapy and chemotherapy. Several cost-effectiveness studies63 have investigated nivolumab monotherapy as second-line treatment for patients with advanced NSCLC. Many studies have compared nivolumab monotherapy with docetaxel monotherapy, and most of those studies have found that nivolumab was not cost-effective compared with docetaxel in a variety of health care settings.62 In addition, nivolumab was not found to be cost-effective compared with erlotinib57 and nivolumab was dominated by atezolizumab .63 However, the results of 2 other studies have suggested that introducing PD-L1 testing or basing treatment on different PD-L1 expression thresholds may improve the cost-effectiveness of nivolumab.59 Overall, the results of the current study support the consensus that nivolumab and/or ipilimumab therapies cannot be considered cost-effective when compared with standard, less expensive therapies.When considering the cost-effectiveness of nivolumab-ipilimumab combination therapy for the treatment of other cancer types, the regimen was found to be cost-effective for patients with advanced renal cell carcinoma depending on the willingness-to-pay threshold used.65 Among patients with lung cancer in particular, a substantial number of individuals present with metastatic disease or develop recurrent disease after initial treatment of local or locoregional disease.6 Thus, a large number of patients with NSCLC will be affected by these high drug costs. Nivolumab-ipilimumab combination therapy was recently approved by the US Food and Drug Administration for use as first-line treatment among patients who have metastatic NSCLC and PD-L1 levels of 1% or higher66 or as treatment in combination with chemotherapy for patients with metastatic NSCLC regardless of PD-L1 status.67 However, Food and Drug Administration approval of a treatment does not guarantee insurance coverage.68 Most insurers provide some coverage for immune checkpoint inhibitors70; however, even with insurance coverage, the high baseline costs of these drugs can lead to high out-of-pocket costs for patients regardless of individual insurance plans.13 Observational research has found an association between the high costs of cancer care and decreased patient adherence, diminished quality of life, and increased risk of substantial debt or bankruptcy.13 Overall, the impact of cost represents an important yet underappreciated and understudied factor associated with the health outcomes of patients with cancer.This study raises several points regarding the implications of the high costs associated with immunotherapy for the treatment of cancer.This study has several limitations. Our model construction primarily used data from a single randomized clinical trial. Cost-effectiveness research would ideally draw from a wider array of resources to construct a more robust predictive model. Treatment responses, quality of life, and costs vary substantially by individual patient, and while our societal viewpoint analysis indicated that nivolumab-ipilimumab combination therapy was not cost-effective, the results may differ for individual patients or for health care delivery settings outside of the CheckMate 227 clinical trial.8 The addition of more comparator treatment arms to this study could, in theory, change the cost-effectiveness of nivolumab-ipilimumab combination therapy; however, the ICER of nivolumab-ipilimumab combination therapy was substantially outside the range considered cost-effective, which suggests that adding more treatment arms would be unlikely to alter our conclusions.Another potential limitation is the heterogeneous array of resources used to inform estimations about costs and health utilities. However, our model was not particularly sensitive to assumptions about cost or health utility, which suggests that including more accurate estimations would be unlikely to change our results. Of note, our analysis considered only dual checkpoint inhibition using nivolumab-ipilimumab combination therapy compared with chemotherapy. Many alternative treatment options (including nivolumab monotherapy and other systemic therapies or immunotherapies) exist for the treatment of advanced NSCLC.This economic evaluation found that nivolumab-ipilimumab combination therapy could not be considered cost-effective as first-line treatment for patients with advanced NSCLC compared with standard chemotherapy despite the increases in overall survival among patients receiving nivolumab-ipilimumab combination therapy. Although immunotherapy represents a promising area in cancer treatment, one must consider the consequences of its high costs to provide the best patient care.