In this paper, we reviewed available evidence on heparin treatment in COVID-19 acute illness and chronic sequalae, focusing on the difference between prophylactic and therapeutic dosage. Coronavirus disease 2019 (COVID-19) is associated with an increased risk of venous thromboembolism (VTE) and coagulopathy, especially in critically ill patients. Endothelial damage induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is emerging as a crucial pathogenetic mechanism for the development of complications in an acute phase of the illness and for several postdischarge sequalae. Heparin has been shown to have a positive impact on COVID-19 due to its anticoagulant function. Moreover, several other biological actions of heparin were postulated: a potential anti-inflammatory and antiviral effect through the main protease (M In December 2019, a novel coronavirus, the SARS-CoV-2, emerged in the city of Wuhan (China) ; odds ratio (OR), 1.06 ;  the ICU . The aut the ICU .p = 0.40), while a statistically significant increase in major or clinically relevant non-major bleeding was reported in the therapeutic group . Notably, no thrombocytopenia was reported. Based on these data, the authors suggest avoiding the use of direct oral anticoagulants (DOACs) unless previously practiced for known indications [The multicentre, randomized AntiCoagulaTlon cOroNavirus (ACTION) trial enrolled about 600 patients and was randomized in a 1:1 fashion therapeutic or prophylactic anticoagulation. The in-hospital therapeutic anticoagulation protocol was the following: rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous UFH for clinically unstable patients, followed by rivaroxaban until day 30. Prophylactic anticoagulation was the standard dosage of enoxaparin or unfractionated heparin, administered only during the hospitalization. As a results, the therapeutic dose showed no significant benefit over the prophylactic one in primary outcomes  on critically ill patients, 534 patients were assigned to therapeutic-dose anticoagulation while 564 were assigned to thromboprophylaxis heparin dose during the hospitalization. The therapeutic dose of heparin showed no significant advantage in reducing mortality compared to prophylactic therapy . Major bleeding rates were slightly but not significantly increased in the therapeutic dose group . Thrombocytopenia was not reported .Such investigators conducted a same fashion multiplatform trial that enrolled 2219 non critically ill patients. Conversely, a significant reduction in mortality and disease intensity with the use of anticoagulant dose compared to prophylactic therapy was observed but with a higher rate of major bleeding (1.9% vs. 0.9%). Thrombocytopenia was not reported .p = 0.31). Major bleeding was comparable (2% of patients in each arm), and thrombocytopenia was not reported [Perepu et al. conducted a 1:1 randomized study in 176 patients comparing enoxaparin at an intermediate dose (1 mg/kg or 0.5 mg/kg twice daily if the body mass index was ≥30) with standard prophylactic therapy in patients with severe COVID-19 (ICU admission and/or evidence of coagulopathy). Enoxaparin dose was administered until hospital discharge or occurrence of a clinical event. No difference was found between the two dosages for the primary outcome  that occurred in 15% of those who underwent the therapeutic dose and 21% treated with the prophylactic dose . Major bleeding events did not significantly differ in the two groups . No cases of thrombocytopenia were signalled [RAPID was an open-label, multicentre randomized trial, that enrolled 465 patients with elevated d-dimer values comparing the standard prophylactic heparin dose (enoxaparin 4000 UI twice daily if BMI > 40) with the standard therapeutic dose. Treatment was continued until hospital discharge, or day 28, or study withdrawal, or death. At 28 days, the therapeutic dose was not significantly associated with a reduction in the primary outcome , but significantly fewer deaths occurred , although this benefit was not observed in ICU patients . Higher but not significant rate of major bleeding occurred with therapeutic dose . Only one case of thrombocytopenia was reported [The multicentre randomized trial HEP-COVID enrolled 257 patients with D-dimer greater than four times the upper limit and with Sepsis-Induced Coagulopathy (SIC) score ≥ 4 and compared the effects of standard anticoagulant dose heparin therapy vs. standard prophylactic dose or standard intermediate therapy during a hospital stay. The primary outcome was VTE, ATE or death from any cause. Therapeutic dose was associated with a reduction in thromboembolic events and death at 28 days , 0.68; 95% CI, 0.49–0.96; p = 0.95). No major bleeding was registered, and thrombocytopenia was not assessed [The BEMICOP Study, an open-label, randomized control trial, compared the therapeutic dose of bemiparin (115 IU/kg daily) versus prophylaxis (bemiparin 3500 IU daily), for 10 days in COVID-19 patients hospitalized with non-severe pneumonia but elevated D-dimer. A total of 65 patients were included in the primary analysis to assess the primary efficacy outcome . The use of the therapeutic bemiparin dose did not improve the outcome as events occurred in 22% of the therapeutic dose group and in 18% of the prophylactic dose group  was compared with the standard prophylactic dose. The study was interrupted prematurely due to slow recruitment. Treatment duration was 7 days in the prophylactic dose group and 9 days in the therapeutic dose group. Although underpowered, the analysis of 183 patients showed no deep vein thrombosis in COVID-19 hospitalized patients in both groups; however pulmonary embolism was observed only in the prophylactic dose group (six patients). No major bleeding and thrombocytopenia events were reported . A meta-analysis conducted by Kow et al. analyzed the data from these randomized trials. The authors acknowledged the biases reported in single studies. Statistical analysis showed no differences in mortality in the therapeutic/intermediate-dose groups versus the prophylactic dose group. A benefit in reducing VTE events was observed in the subgroup of patients with severe COVID-19 without a significant increase in bleeding. The results suggested a benefit of anticoagulant therapy over the prophylactic dose. The failure to reduce mortality in severe patients seemed to be due to a delayed start of therapy. No trial evaluated the risk of individual bleeding; therefore, this could explain the observed increase in major bleeding .We also found meta-analyses of non-randomized trials. Hasan et al. included 12 studies on patients admitted to the ICU and highlighted a high prevalence of thromboprophylaxis failure; therefore, they suggested an individualized approach rather than a fixed prophylactic dose .A second meta-analysis on 11 studies was conducted by Sridharan et al.  in hospi9/L, and a prothrombin time  <  14 s, regardless of comorbidity, sex or age [A third meta-analysis that investigated the impact on mortality using the prophylactic heparin dose was performed by Abdel-Maboud et al. Authors included, in the final analysis, five studies and showed a positive effect of prophylactic dose only in patients with moderate symptoms and a combined D-dimer  >  3 µg/L, a platelet count  >  100 × 10x or age .Parisi et al. analyzed 29 studies with very heterogeneous data both on the type of anticoagulant used and on the dosage. Despite the limitations of the examined sample, there was a reduction in mortality in the group that underwent anticoagulant therapy; however, an increased percentage of bleeding was observed. The authors suggested that it is advisable to use prophylactic doses in non-severe diseases .As discussed above, the risk of ATE and VTE in patients with COVID-19 extends beyond their hospitalization. The role of heparin for postdischarge prophylaxis was investigated by some authors. The COVID-19 Research Consortium of our health system(CORE-19) registry assessed 90-day postdischarge VTE and ATE: the use of anticoagulants, mostly prophylactic doses, was associated with a 46% decrease in VTE, but the subgroup of patients who received heparin thromboprophylaxis was small as enoxaparin was used only in 1.3% of patients . In a retrospective analysis conducted in hospitalized patients with symptomatic COVID-19 infection who were discharged, no VTE events occurred in those who received extended prophylaxis; however, enoxaparin was used only in 12.9% of cases . To dateData from several studies confirmed the increased incidence of VTE in COVID-19 patients and its impact on mortality, especially in ICU patients. An increase in bleeding was also observed ,70,71. TAlthough immune thrombocytopenia has emerged as a complication of COVID-19 , low plaThe American Society of Hematology (ASH) guideline panel suggested the prophylactic versus intermediate or therapeutic dosage for patients with acute or critical COVID-19 illness without VTE  , and a sThe impact of other anticoagulants in improving the outcome of COVID-19 has been evaluated. In two studies the prophylactic dose of Fondaparinux (2.5 mg daily) showed similar efficacy and safety compared to enoxaparin prophylactic dosage ,79. ConvAlso, the use of DOAC in COVID-19 was investigated. A recent meta-analysis of 12 studies involving 30,646 patients concluded that previous DOAC therapy at time of COVID-19 diagnosis did not improve clinical outcomes . FurtherPostdischarge thromboprophylaxis is not recommended, although it could be considered in patients at high risk of VTE and low risk of bleeding . Only thThe main limitation of the trials is due to the pandemic scenario in which recruitment and follow-up were challenging in several countries. Therefore, most of the studies included a limited number of patients with a consequent reduction of statistical power.Second, the criteria used to classify patients into critically ill or non-critically ill differed across the studies. Third, the short duration of study treatment limits the evaluation of long-term impact. Finally, the intrinsic limitation of retrospective studies included in some meta-analyses encompass selection bias and confounding bias.Heparin plays a central role in COVID-19 treatment as demonstrated in several randomized clinical trials, although with some limits due to the COVID-19 related pandemic. The appropriate dose of heparin is still being debated and a reasoned approach according to clinical scenarios is necessary. According to the most updated guidelines, the prophylactic dose is recommended in all hospitalised patients unless contraindicated, while the therapeutic dose could be considered only in non-pregnant patients requiring low-flow supplemental oxygen, with increased D-dimer levels and low bleeding risk. In case of thrombocytopenia, the prophylactic dose of fondaparinux could be considered. In patients previously treated with DOAC for underlying conditions, these medications should be continued after a diagnosis of COVID-19.Heparin may also have a role in the prevention of postdischarge COVID-19 sequelae in the presence of high-risk clinical features that raise the risk of thrombotic complications.


In Taiwan, the incidence of upper-tract urothelial carcinomas (UTUCs) is higher than in western countries (20%–31% vs. 5%–10%), as is bilateral disease. The standard management for high-grade UTUC is radical nephroureterectomy with bladder cuff excision and regional lymphadenectomy. The challenges in managing bilateral UTUCs are how to retain renal function and avoid permanent hemodialysis. We present two cases of developed bilateral high-grade renal pelvis urothelial carcinoma, cT3N0M0 stage III, that revealed excellent results in tumor regression after three cycles of half-dose pembrolizumab. One case received unilateral retroperitoneal laparoscopic nephroureterectomy with bladder cuff excision; thereafter, renal function has been good until now, and the remaining right kidney has been free of tumor recurrence in the 3 years of follow-up. The other patient, however, expired from an immune-related adverse event (irAE) 22 days after the third cycle of pembrolizumab, although tumor remission was evident also. Neoadjuvant pembrolizumab alone could be a potential strategy in positive of selected biomarkers for high-grade bilateral UTUC with remaining neglectable nephrotoxicity and may avoid permanent hemodialysis. In Taiwan, the incidence of upper tract urothelial carcinomas (UTUCs) is higher than in western countries (20%–31% vs. 5%–10%) ; moreoveAn 81-year-old woman with a history of hypertension and Alzheimer’s disease had presented with intermittent painless gross hematuria for 1 year. She had not consumed alcohol nor smoked cigarettes, and there was no cancer history in her family. Her computed tomography (CT) of the abdomen revealed a tumor in the bilateral renal pelvis with renal parenchyma invasion  22 days after the third cycle because of low abdominal pain for 2 days accompanied by decreased urine output and dysuria without fever, chills, tachypnea, hematuria, or diarrhea. She was found to have acute decompensated hepatitis, acute pancreatitis, and acute-on-chronic kidney disease. We prescribed methylprednisolone due to grade 3 immune-related adverse event (irAE) being highly suspected. Unfortunately, her condition deteriorated quickly; she developed sinus bradycardia and hypothyroidism within 29 days and eventually expired.UTUCs are rare in western countries and make up only 5%–10% . By contThe standard management for high-grade UTUC is radical nephroureterectomy with bladder cuff excision and regional lymphadenectomy . Our repp = 0.002) and fewer grade 3–5 treatment-related adverse events (AE) in pembrolizumab-treated patients compared to chemotherapy (15.0% vs. 49.4%) in recurring or progressing UC after platinum-based chemotherapy  compared to chemotherapy; for example, Bellmunt et al. demonstrated longer median overall survival  in 42% of patients and downstaging (<ypT2) in 54% after receiving three cycles of 200 mg pembrolizumab before radical cystectomy, and also revealed better response rate in patients with PD-L1 CPS ≥10% and was safely administrated .ICI has already changed our clinical approach in advanced or metastatic bladder UC. However, there is limited evidence of kidney sparing approaches in high-grade UTUC, probably because of rare incidence in western countries, with bilateral high-grade not even being mentioned. Since the experience in PURE-01 is promising and possesses lesser adverse events than chemotherapy, we expected the same rationale would be matched to avoid hemodialysis in bilateral UTUC patients.We prescribed half-dosage (100 mg) pembrolizumab because the patients’ weights were 43 and 45 kg only. In our experience of these two cases that developed bilateral high-grade renal pelvis UC, both had an excellent result in tumor regression after three cycles, even at a half-dosage (100 mg) of pembrolizumab compared to the recommended dose. One patient had the right kidney preserved with complete remission and received a left nephroureterectomy with bladder cuff excision for the partially responding tumor and has avoided lifelong hemodialysis without recurrence in 3 years of follow-up until now. Accordingly, a patient with bilateral UTUC with positive selected biomarkers might benefit from neoadjuvant pembrolizumab as the only strategy to avoid lifelong hemodialysis.Unfortunately, the other case expired from severe irAE even though having a great response to pembrolizumab; accordingly, there remains a risk of 15%–17% grade 3–5 treatment-related adverse events with pembrolizumab , 19. ForAccording to the existing evidence of ICI in treating advanced or metastatic UC and our experiences, neoadjuvant pembrolizumab alone could be a potential strategy in PD-L1 expression high-grade bilateral UTUC with remaining neglectable nephrotoxicity, is easy to use, and, in particular, could avoid lifelong hemodialysis. Additionally, there is no consensus on the booster of immunotherapy after radical procedures, although, in our limited experience, two booster cycles of pembrolizumab appeared to suffice in our patients. More prospective clinical trials and validations are needed to build up standard management and biomarkers for UTUC to offer more benefits in bilateral disease, solitary kidney, or chronic kidney disease. After familiarity with irAE of immunotherapy in different specialties is established, the benefits of immunotherapy will outweigh the disadvantages. Immunotherapy is a two-sided knife for PD-L1-selected bilateral UTUC patients.Her family is glad that the patient is alive and has avoided hemodialysis until now in the first case. However, in the second case, her daughter understood that avoidance of hemodialysis was her mother’s wish, and although we had great oncology outcomes, awful adverse events happened despite us doing our best. Both patient families feel that if this treatment could ensure freedom from hemodialysis, they would like to choose such an innovative treatment strategy.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Chang Gung Medical Foundation- Institutional Review Board (CGMF-IRB) (IRB no. 202100779B0). The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.W-NC wrote the original draft, constructed the figure, and performed the literature review. Y-CH and D-RH assisted in the literature review and revision of the manuscript. C-SC provided clinical materials and final editing of the manuscript. 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 emergence of Coronavirus disease 2019 (COVID-19) has changed the world in an irrevocable direction. The changes have affected all vital sectors, including finance, education, communications, research, and, undoubtedly, the medical practice. Every field related to human health explored how to escalate its performance and updated its research priorities to respond to the situation imposed by the devastating pandemic. Pharmacogenomics (PGx) is not an exception. Multiple researchers in the field investigated the available PGx information related to medications used in COVID-19 management, and various reviews have appeared since late 2020 till today . Most ofClinicalTrials.gov at the time of publication. The authors reviewed the pharmacogenetic biomarkers found to be associated with these drugs. None of the studied drugs had approved PGx-guided dosing guidelines, and few had moderate to low significance PGx associations. The illustrated candidate response and toxicity biomarkers were retrieved from previous research in diseases other than COVID-19. The authors highlighted that no PGx data is available from SARS-CoV2 patients yet.The earliest publication of SARS-CoV2 treatment PGx was a literature review by Takahashi and colleagues , which wHLA-B*57:01 to exemplify the success of pharmacogenomics implementation in infectious diseases. At the same time, they underscored the time between identifying HIV and recognizing this PGx association and its implementation success (Nevertheless, Takahashi and colleagues used the association between abacavir, the anti-HIV agent, and  success . CompareOn the other hand, and due to limited PGx data for most of the antiviral drugs re-purposed for COVID-19, some reviews illustrated the available sporadic reports about PGx associations from the literature . The lisSLCO1B1*4 was recorded as a candidate effector on lopinavir clearance. The variations in this allele frequency among populations were briefly highlighted, and its frequency was reported as 14% in Europeans, 6% in Africans, and 0.3% in East Asians (SLCO1B1 allele could be associated with increased clearance of lopinavir in these ethnicities. Although there has been a recommendation against using lopinavir in SARS-CoV2 in the early 2021 (SLCO1B1 is active in the transportation of other antivirals, like atazanavir.One common outcome of the COVID-19-PGx reviews is listing the candidate PGx effectors on drugs used for SARS-CoV2. For example, t Asians . Howevert Asians . The higrly 2021 , SLCO1B1CYP3A4/5, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, ABCB1, and SLCO1B1, among others. These specific genes illustrate a wide range of inter-population and inter-ethnic variability, as reported in studies from Africa and Southeast Asia (Furthermore, in a more recent SARS-CoV2 drugs PGx review , the autast Asia . Table 1ast Asia . HoweverAccording to the mentioned COVID-19 PGx reviews, a significant limitation hindering PGx data use for COVID-19 patients is the unavailability of the patient’s PGx profile when admitted for acute illness. Pre-emptive PGx testing would be one solution for this limitation, while providing a reactive point-of-care PGx testing is another. Stevenson and colleagues have shown that in a cohort of patients hospitalized for COVID-19, nine in 10 patients had at least one order of a drug with a PGx recommendation. Moreover, through a simulation analysis, the authors found that 17 treatment modifications per 100 patients would be feasible if pre-emptive PGx data were available in the EHRs of these patients at the time of admission. The authors also emphasized that the multigene-PGx results are projected to positively impact patients’ healthcare years after hospital discharge .In a similar attempt to explore the PGx-data potential impact on COVID-19 outcomes, Sahana and coworkers analyzed the PGx variants from the “IndiGen” dataset, the dataset of 1000 + Indian whole genome sequences. The authors concluded that the population-specific PGx variation landscape, if utilized, could have contributed to designing population-specific clinical trials and expediting decision-making throughout the pandemic .Another critical point to consider, specifically during a pandemic when few therapeutic options are available, is that any PGx testing is limited by proving its cost-effectiveness . HoweverNevertheless, even if the previous controversial points were resolved and the PGx data is available at the point of admission, it cannot be utilized unless clinical guidelines are available at the hands of the clinician. This fact brings us back to the difficulty in generating such guidelines without extensive prospective studies, which should prove cost-effectiveness besides positive or equivalent clinical outcomes. There is a severe need to break this vicious circle before a new pandemic strikes. Utilizing novel machine learning approaches  and inteCYP2C19-remdesivir interaction exemplifies the potential gains of the availability of PGx information in patients’ health records.Interestingly, COVID-19 patients’ DNA biorepositories have already been established . While tHerein, the minimal COVID-19 PGx available data could be seen as an unprecedented motivation to accelerate the PGx implementation process. With the decrease in genetic testing costs, the increase in the number of available techniques for genotyping, and the evolution in data science that allows optimal data storage and making sense of genetic information, there is an immense need to consider PGx testing in the population scale and maintain this information in medical health records. Having this information at the point of admission due to an acute illness or in the mid of a pandemic is, undoubtedly, a rich source for evaluating the practice of precision medicine in real life. While developed countries with more robust healthcare systems can be considered the ultimate candidates for taking the lead in PGx implementation, developing countries and those with emerging economies inhabited by poorly studied communities should explore investing in population-PGx as a plausible approach to achieving cost-effective precision health care.To conclude, before the next pandemic actively hits, there is a need to seriously consider preemptive PGx testing implementation in different populations. Postponing such initiatives due to doubts about cost-effectiveness or performance feasibility threatens time, money, and probably the lives of people who could have been spared from unnecessary treatments or adverse drug events.


The optimal duration of dual antiplatelet therapy (DAPT) after biodegradable-polymer (BP) everolimus-eluting stent (EES) implantation remains uncertain.  This study analyzed 793 patients who underwent percutaneous coronary intervention (PCI) with BP-EES in 10 cardiovascular centers in Korea between July 2016 and January 2018. Using the prescription data at 6 months post-PCI, we divided these patients into two groups, namely, short-DAPT and prolonged-DAPT groups, which underwent DAPT for 6 and > 6 months of PCI, respectively. The primary endpoint, which included mortality, myocardial infarction, or target-vessel revascularization at 2 years, was compared by propensity score (PS) matching between the two groups. P = 0.648). Likewise, no difference was found regarding mortality, cardiac mortality, myocardial infarction, target-lesion failure, target-vessel failure, and bleeding events defined by the Bleeding Academic Research Consortium and Thrombolysis In the Myocardial Infarction classification. Meanwhile, one patient in the short-DAPT group had definite stent thrombosis at 364 days post-PCI. Subgroup analysis showed that several anatomical and procedural factors were not significantly related to DAPT duration. Most patients (77.4%) in both groups were prescribed clopidogrel at discharge.  Out of the 793 patients, 283 matched pairs were identified by PS matching. Out of this matched population, 405 (71.6%) patients had an acute coronary syndrome. The primary endpoint did not differ in 2 years between the short-DAPT and prolonged-DAPT groups  DAPT. The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) remains controversial. In the current US and European guidelines, the recommended duration of DAPT is ≤6 months for stable coronary artery disease and ≤12 months for acute coronary syndrome (ACS) after PCI with a drug-eluting stent (DES) . NonetheThe polymer, which is a coating material on the stent's metallic surface, carries the needed amount of antiproliferative drugs for a specific time . It enabμm) with BP  at the outer surface of the scaffold for everolimus (100 μg/cm2) release. [The DC-Synergy registry is a prospective all-comer real-world registry that has been recording patients over 18 years of age who underwent PCI with BP-EES in 10 cardiovascular centers in Korea since July 2016. Patients registered between July 2016 and January 2018 were enrolled in this study. BP-EES , which was used in this study, was characterized by a thin platinum-chromium platform  can be administered beyond 6 months after PCI. Information such as patient demographics, combined comorbidity, angiographic characteristics, laboratory findings, and follow-up outcomes was obtained from the medical records acquired during regular visits or telephone interviews. Data were collected in a web-based, dedicated electronic case-reporting form and periodically monitored by research personnel.Treatment strategies that include decision-making in terms of PCI, access route, devices to be used for the procedure, and the number, length, and diameter of the stent were at the discretion of the attending interventional cardiologists according to each patient's demographic and angiographic factors. DAPT was initiated one day before the elective PCI or just before the emergent PCI. Medical treatment after the index procedure was guided by current guidelines and established standards of practice. After the index PCI, the patients were followed up at 1 month, 3 months, 6 months, 1 year, and annually thereafter. DAPT was prescribed for at least 6 months, and its prolonged use or switch to single antiplatelet therapy (SAPT) was at the discretion of the attending physician. Any single antiplatelet agent such as aspirin (100–325 mg once daily) or P2YShort-DAPT was defined as the use of DAPT for 6 months after PCI. The duration was based on the prescription data at 6 month follow-up. If there was a prescription switch from DAPT to SAPT at 6 months follow-up, those were categorized as the short-DAPT group, whereas those who continued DAPT >6 months were categorized as the prolonged-DAPT group.https://precisedaptscore.com/).The primary endpoint of this study was the composite of all-cause mortality, myocardial infarction (MI), or target-vessel revascularization (TVR) at 2 years after the index procedure. The secondary ischemic endpoints of interest included composites of cardiac mortality, MI, or TVR; all-cause mortality or MI; and cardiac mortality or MI; and all-cause mortality, cardiac mortality, MI, TVR, target-lesion revascularization (TLR), and definite or probable stent thrombosis at 2 years. Cardiac mortality was defined as any death caused by a cardiovascular problem or if there was no identified cause of death. MI was defined as cardiac enzyme increase beyond the upper reference limit, with ischemic symptoms or signs that occurred spontaneously during the follow-up. Periprocedural MI was not accounted for the event in this study. TVR was defined as any revascularization procedure of the coronary vessels that were the target of the index procedure, and TLR was defined as the repeat revascularization within a 5 mm border of the index procedure stent. Bleeding events were recorded according to the Bleeding Academic Research Consortium (BARC) and Thrombolysis in Myocardial Infarction (TIMI) classification , 19. Fort-test for the continuous variables. To compensate for the non-randomized design of this study, we performed 1 : 1 propensity score (PS) matching to adjust the selection bias of DAPT prescription at 6 months with a caliper of 0.2. The covariates that were input in the logistic regression model determining the PS were as follows: age, sex, initial presentation , atrial fibrillation, body mass index, hypertension, diabetes, diabetes on insulin, current smoker, dyslipidemia, previous MI, congestive heart failure, peripheral vascular disease, chronic kidney disease, chronic kidney disease on hemodialysis, left ventricular ejection fraction, target vessel, multivessel stent, stent number, mean stent diameter, stent length, access route, complete revascularization, and discharge medications . To assess the appropriateness of the adjustment, we used standardized mean differences between both groups after PS matching. Survival curves and event rates in the matched population were estimated using the Kaplan-Meier method. The risk of short-DAPT on clinical outcomes of interest was investigated and compared with that of prolonged DAPT by using Cox proportional hazards models. The time-dependent effect of DAPT duration during the follow-up period was assessed by landmark analysis in the survival curve. All reported P values were two-sided, and P < 0.05 was considered statistically significant. All statistical data were analyzed using the R software .Patient demographics and procedural characteristics are presented as means with standard deviations in continuous variables and as numbers with percentages in categorical variables. Comparisons between groups were performed using the Pearson's chi-square test for the categorical variables and the student's P=0.165), and 15.0 ± 8.7 and 15.1 ± 8.4 in short-DAPT and prolonged-DAPT groups in the matched population (P=0.965).Of the 972 patients enrolled in the DC-Synergy registry between July 2016 and January 2018, 179 were excluded  in the matched population (P=0.455). The TLR rates were similar in both groups. Only one patient from the short-DAPT group manifested definite stent thrombosis at 364 days after PCI and underwent repeated intervention for the treatment. Bleeding events  occurred in 20 patients in the matched population within 2 years. At 2 years, the two groups demonstrated no differences  during the entire follow-up period and after 6 months of PCI  in the landmark analysis. Supplemental P=0.030) than in the prolonged-DAPT group, which had a significantly higher rate of TVR .For the primary endpoint, the composite of all-cause mortality, MI, or TVR occurred in 19 (7.5%) and 22 (8.3%) patients in the short-DAPT and prolonged-DAPT groups at 2 years (pulation . The rat12 inhibitors (ticagrelor and prasugrel)  in the short-DAPT group.In both groups, 77.4% of patients in the matched population were prescribed clopidogrel at discharge, whereas 22.6% were prescribed potent P2YIn this study involving a real-world population, we evaluated the clinical efficacy and safety of short-DAPT (6 months) in patients who underwent PCI with BP-EES. The major findings of the study are as follows: (1) compared with prolonged-DAPT, short-DAPT was related to similar efficacy in preventing ischemic cardiovascular events at 2 years after PCI; (2) short-DAPT was not related to reduced bleeding outcomes defined by BARC and TIMI classification; and (3) short- and prolonged-DAPT strategies had no significant interaction with several clinical subgroups.The role of DAPT is to reduce the risk of ischemic events, especially stent thrombosis, during the early phase after PCI with DES. Considering those patients who have an increased risk of ischemic events, current guidelines recommend the use of DAPT for 12 months in patients with ACS and 6 months in patients with stable angina . With th12 inhibitors, usually ticagrelor, for maintaining SAPT. Our study demonstrated that a shorter DAPT duration followed by SAPT (mostly aspirin) could be a safe option after PCI for patients with ACS (70%), consistent with the previous randomized trials.Approximately 70% of our study patients had ACS at baseline. The results demonstrated similar rates of the ischemic composite endpoints between the short- and prolonged-DAPT groups after PCI with BP-EES. The ischemic and bleeding risks vary over time after PCI, and the ischemic risk is greater in the early phase following the ACS event. Thus, current guidelines for ACS recommend prolonged DAPT, which is twice as long as that for stable angina patients , 22. RecConsidering the varying risks of ischemia or bleeding events among patients, the duration of DAPT after PCI should be carefully selected for each patient. Current guidelines recommend a shorter duration of DAPT in patients with a high-bleeding risk in both the ACS and stable angina populations , 3. In c12 inhibitors is favored when switching from DAPT to SAPT. Therefore, our results should be interpreted with caution because most SAPT was prescribed with aspirin, and potent P2Y12 inhibitors were used in a minimal number.First, there is the inherent limitation of the nonrandomized design in this study. Although PS matching analysis was used to adjust for potential selection bias, unmeasured confounders that may have affected the results could not be excluded. In addition to the baseline characteristics, comorbidities associated with a worse prognosis were observed more frequently in the prolonged-DAPT group. Since the duration of DAPT use was determined by the attending physician, there may be a systematic bias across the study that low-risk patients were selectively treated with short-DAPT and high-risk patients were more frequently treated with prolonged-DAPT. Second, the initial design of this registry was not powered to calculate the differences in clinical outcomes between the short-and prolonged-DAPT groups. In addition, the lack of statistical differences in the clinical outcomes in both groups could be underestimated by the small sample size with low clinical event rates. Furthermore, bleeding events could not be evaluated because of the extremely low incidence during the study follow-up. Third, short and prolonged DAPT were categorized only by the prescription data at 6 months after PCI. Therefore, the compliance of the study patients in the administration of all antiplatelet agents could not be assessed in the study result. Fourth, different types and potency levels of antiplatelet agents were used during study follow-up because antiplatelet agents were selected according to the discretion of the attending cardiologists in the real-world clinical practice. According to the results of recent randomized trials, the use of potent P2YIn this study, which compared the clinical outcomes of short-DAPT (6 months) and prolonged-DAPT (>6 months) in patients who underwent PCI with BP-EES, there were no differences in cardiovascular events rate during 2 years of follow-up. However, patients in the short-DAPT group undergoing multivessel stenting tended to have worse adverse events than the prolonged-DAPT group. The bleeding event was not different in both groups, but the event number and rate were extremely small.


The effectiveness of inactivated vaccines (VE) against symptomatic and severe COVID-19 caused by omicron is unknown. We conducted a nationwide, test-negative, case-control study to estimate VE for homologous and heterologous (BNT162b2) booster doses in adults who received two doses of CoronaVac in Brazil in the Omicron context. Analyzing 1,386,544 matched-pairs, VE against symptomatic disease was 8.6%  and 56.8%  in the period 8–59 days after receiving a homologous and heterologous booster, respectively. During the same interval, VE against severe Covid-19 was 73.6%  and 86.0%  after receiving a homologous and heterologous booster, respectively. Waning against severe Covid-19 after 120 days was only observed after a homologous booster. Heterologous booster might be preferable to individuals with completed primary series inactivated vaccine. This study investigates the effectiveness of COVID-19 vaccine boosters following a primary series of CoronaVac vaccination. Using data from Brazil during the Omicron wave, the authors show that boosters provided protection against severe disease, with higher effectiveness from a BNT162b2 than CoronaVac booster. Since then, accumulating evidence has demonstrated the importance of waning protection following primary series completion6, and decreased effectiveness of current vaccines to variants of concern (VoC), in particular the Omicron (B.1.1.529) variant7. Delineating the effectiveness of the range of booster vaccination strategies is therefore critical for guiding national and global policy8.The substantial initial protection of primary series Covid-19 vaccines against moderate and severe Covid-19 has been demonstrated through randomized clinical trials and observational studies10, leaving significant evidence gaps regarding inactivated vaccine products. Inactivated vaccines are widely used, particularly in low- and middle-income countries, and represent half of the administered doses of Covid-19 vaccines worldwide as of Jan 202211. Large Omicron epidemics associated with severe cases and deaths have occurred in regions, most recently Eastern Asia, where inactivated vaccines have been extensively administered12. Brazil initiated booster vaccination in September 2021, after Delta VoC began to dominate in the country and three months before Omicron dominance5. Evidence concerning the effectiveness of inactivated vaccines with homologous or heterologous boosters is critically needed to inform vaccine policies in countries that used these vaccines in their initial rollout.The majority of the existing vaccine effectiveness evidence is for mRNA vaccines and adenoviral vectored vaccines, both as the primary series and as booster dosesWe evaluated the vaccine effectiveness of CoronaVac and BNT162b2 booster doses among Brazilian adults who completed the primary series of the CoronaVac vaccine in a nationwide test-negative case-control study. Our primary analysis focused on the period from December 25, 2021 to April 22, 2022, when circulation of the Omicron variant was predominant, and compared these findings with those from the prior period, from September 6, 2021, to December 14, 2021, when the Delta variant was predominant in the country.During the study period, there was a low incidence of Covid-19 cases and hospital admissions or deaths during the Delta wave compared to earlier periods in Brazil, until the end of December 2021, which corresponded to the introduction and spread of the Omicron variant . However, a heterologous booster dose of BNT162b2 afforded a substantial increase in protection against severe disease in all age groups, including the elderly with age ≥75 years, compared to the primary series and some protection against symptomatic disease, albeit of uncertain duration. Although the direct comparison between homologous and heterologous booster is not straightforward because of the potential confounding factors between the individuals who received each vaccine , and the difference in effectiveness observed between homologous and heterologous boosters is very unlikely to be explained by unmeasured confounding alone. Nevertheless, our results could be biased through this mechanism, and the direction of bias is unclear. Finally, differences in effectiveness and waning patterns by age could be driven by other factors, including occupational exposure  and personal risk mitigation behavior20.Some limitations should be acknowledged. The data available for this study was collected as part of Brazil’s passive surveillance efforts for Covid-19, so important covariates may be missing or incomplete. As usually done in population-based studies with record linkage, we considered those individuals not linked to the vaccination database as unvaccinated, so we can have some degree of misclassification on vaccination status. We did not expect a relevant proportion of misclassification because the databases are centrally managed by the same data guarantor and we excluded few inconsistencies between and within databases. The distribution of RT-PCR tests and antigen tests, which have different sensitivity, changed over the course of the study period, which could have led to a decrease in estimated VE during the Omicron period through misclassification. However, a sensitivity analysis restricted to RT-PCR tests produced similar results. In the same topic, a higher vaccine effectiveness was observed in the main analysis against symptomatic Covid-19 during Omicron period (VE: 24.6%) in the period 0-13 days after the first dose (“bias indicator”) compared with the estimate in the sensitivity analysis restricted to RT-PCR tests (VE: 4.6%), showing evidence for potential misclassification of rapid antigen tests. In all analyses the overall vaccine effectiveness estimates were consistent and we don’t expect these biases would change considerably the message of this study. In addition, the test-negative controls may have been different during the Omicron and Delta periods, which could explain some of the difference in VE estimates. In particular, a higher proportion of controls were hospitalized or died during the Delta period , Oxford-AstraZeneca ChAdOx1 nCoV-19 (two doses), Pfizer BNT162b2 (two doses), Janssen Ad26.COV2.S (single dose), and heterologous combinations of the above products in periods of vaccine shortage. All four vaccine products were administered as a homologous or heterologous booster dose. There was no differential recommendation for which vaccine to be administered, except a suggestion for BNT162b2 if available. The booster vaccination followed an age-prioritization scheme. The interval between second and booster doses was initially six months and was subsequently shortened to four months during November 2021 in some states and nationally on December 20, 2021. The proportion of individuals with a primary series of CoronaVac who received a booster dose of Ad26.COV2.S or ChAdOx1 nCoV-19 was small; therefore we limited our analysis to booster doses of CoronaVac and BNT162b2.28. We obtained individual-level vaccination status from the national vaccination database (SI-PNI). Notification to these three systems is compulsory in Brazil. The three databases have a unique identifier after pseudo-anonymization by the Ministry of Health. Additional information is available on Supplementary Table We obtained individual-level information on Covid-19 outcomes from two national surveillance databases in Brazil: e-SUS and SIVEP-Gripe. e-SUS collects information of any individual suspected to have mild Covid-19 syndromic illnesses, including those who were not tested, tested negative and tested positive. SIVEP-Gripe collects information on any severe acute respiratory infection, including all Covid-19 hospitalizations and deaths29 during the study period. We excluded individuals with missing or inconsistent information on age, sex, municipality of residence, and on vaccination and testing status and dates. We excluded RT-PCR/antigen tests that were not collected within 10 days of symptom onset to avoid potentially misclassification, positive or negative RT-PCR/antigen tests with a positive RT-PCR/antigen test in the previous 90 days to capture only incident infections and avoid a second positive test because of prolonged viral shedding, and negative RT-PCR/antigen tests with a positive RT-PCR/antigen test occurring in the following 14 days because of likely false-negative test in the first negative test. For individuals who received multiple RT-PCR or antigen tests during the study period, we included all eligible tests up to and including the first positive test . The number of RT-PCR/antigen tests performed during the study period in Brazil is shown in Supplementary Fig. The study population was adults aged ≥18 years) residing in Brazil, and who underwent SARS-CoV-2 RT-PCR or rapid antigen testing associated with symptomatic illness8 years rTo assess waning of the booster doses over time since administration, we performed a separate, secondary, case-control analysis on the same study population, restricting to cases and controls who received a primary series of CoronaVac and received an RT-PCR/antigen test at least six months after their second dose, i.e. when eligible for a booster dose. The study design and matching procedure was otherwise the same.Cases were defined as those from the study population who had Covid-19 symptoms, defined by the presence of at least one symptom: fever, sore throat, headache, cough, chills, runny nose, dyspnea, anosmia, and ageusia, and a positive SARS-CoV-2 RT-PCR/antigen test result. Eligible controls were defined as those from the study population who had Covid-19 symptoms as defined by cases, and a negative SARS-CoV-2 RT-PCR/antigen test result. Finally, we excluded all RT-PCR/antigen tests that were obtained after receipt of a primary series of ChAdOx1 nCoV-19, BNT162b2 or Ad26.COV2.S vaccines.20.We matched each case with one control according to the age (± 10 years), sex, municipality of residence, variant period, and RT-PCR/antigen test sample collection date (± 10 days). The algorithm used for the continuous variables (age and test sample collection date) was nearest neighbour matching. After identification of each case, we randomly chose one control from the set of all eligible matching controls, allowing for the replacement of controls. We performed a sensitivity analysis on the matching approach by creating strata of unique combinations of the matching factors . The numbers of cases and controls per stratum are not pre-specified, and strata with no cases, or with no controls, were excluded. This leads to varying ratios of cases to controls. This was done to use all available information, reducing how often unmatched cases or controls needed to be discarded and no case or control appears in more than one stratum, thus dealing with the potential issue related to replacement. To improve the computational performance of the models while retaining the majority of cases, large strata were reduced in size by dividing into smaller strata. In strata with more controls than cases, each stratum allowed a case to be matched to up to ten controls, and vice versa. For strata with at least ten times as many controls as cases, excess controls were discarded, and vice versa. In this way, strata sizes varied from two to eleven31. Symptomatic Covid-19 includes mild and severe cases. Severe Covid-19 was defined as hospital admission and death with severe acute respiratory infection due to SARS-CoV-2 (positive RT-PCR/Antigen test). For the analyses of symptomatic and severe Covid-19, we considered the date of respiratory sample collection as the date of the event. There are several choices of controls for severe outcomes, including community nonsyndromic controls, community syndromic controls, and hospitalized test-negative controls with or without symptoms33. Each has their advantages and disadvantages in how well they represent the source population in their uptake of Covid-19 vaccination. We choose a priori to use community and hospitalized syndromic controls as we agreed these are the controls that better represent the vaccination status in the Brazilian setting. Additionally, we chose syndromic controls to reduce the bias in testing behaviour25, as those tested in the absence of symptoms are more likely to be part of special groups of individuals . The reference group was unvaccinated individuals. For the secondary analysis assessing waning effectiveness, we estimated the relative vaccine effectiveness (rVE)34, using booster eligible (≥180 days after the second dose) CoronaVac recipients as the reference group, and stratified the time since booster administration by 8–59 days, 60–89 days, 90–119 days and ≥120 days. We used RT-PCR/Antigen test respiratory samples to define cases and controls in any effectiveness analyses. Cases and controls that were not linked to the vaccination database were ascertained as unvaccinated.We estimated the vaccine effectiveness of booster doses of CoronaVac and BNT162b2 against symptomatic Covid-19 in the 0-7 days, 8-59 days and ≥60 days after the booster dose. We also estimated the vaccine effectiveness of a booster dose against Covid-19 hospitalization and/or death by restricting the analysis population to case-control pairs in which the case was hospitalized or died30. Because age is a strong determinant of Covid-19 outcomes, we adjusted for age  after matching to control for potential residual confounding within age bands. We also adjusted for chronic comorbidities , self-reported race, and any previous symptomatic event that were reported to the surveillance systems . We adjusted for self-reported race because it is a main surrogate of socioeconomic status and associated with risk of infection and outcomes in Brazil3. Prior SARS-CoV-2 exposure is defined as notified acute respiratory infection or positive SARS-CoV-2 test result prior to the sampled RT-PCR/Antigen test. This variable is our best surrogate of previously confirmed or suspected infection of SARS-CoV-2. We considered the vaccine effectiveness estimates for the 0-13 days after the first dose as a “bias indicator”, because it is expected that vaccines have no or limited effectiveness for this period35.We used conditional logistic regression to estimate the adjusted odds ratio (aOR) of vaccination comparing cases and controls, and (1−aOR)*100 provided an estimate of vaccine effectiveness under the assumptions of a test negative design36. We conducted the same analyses using only RT-PCR tests as a sensitivity analysis, to address potential misclassification. Finally, we conducted two posthoc sensitivity analyses, evaluating vaccine effectiveness in the main analysis population defining severe Covid-19 as use of respiratory support, intensive care admission, and death with severe acute respiratory infection due to SARS-CoV-2 (positive RT-PCR/Antigen test); and evaluating relative vaccine effectiveness in the main analysis population further adjusting by month of second dose as a factor in the model.We conducted an analysis of vaccine effectiveness within age subgroups  by adding an interaction term with the vaccination category. Because the analysis period incorporated a Delta (B.1.617.2)  and Omicron  period, we conducted separate analyses in each time period. We defined the end of the Delta period as when national Omicron VoC prevalence amongst sequenced genomes reached 25% and the beginning of the Omicron period as when the prevalence reached 75% in the GISAID database37All analyses were done in R (v.4.1.2)Further information on research design is available in the Supplementary InformationReporting Summary


Maternal lipid levels in early pregnancy are associated with maternal health and foetal growth. It is however unclear if maternal lipids in early pregnancy can be used to predict childhood lipid levels. The aim of this study is to assess the association between maternal and offspring childhood lipid levels, and to investigate the influence of maternal BMI and diet on these associations.This study included 2692 women participating in the Generation R study, an ongoing population-based prospective cohort study from early life onwards. Women with an expected delivery date between 2002 and 2006 living in Rotterdam, the Netherlands were included. Total cholesterol, triglycerides and high-density lipoprotein cholesterol (HDL-c) were measured in early pregnancy . Low-density lipoprotein cholesterol (LDL-c), remnant cholesterol and non-HDL-c were calculated. Corresponding lipid measurements were determined in 2692 children at the age of 6  and 1673 children 10 years . Multivariate linear regression analysis was used to examine the association between maternal lipid levels in early pregnancy and the corresponding childhood lipid measurements at the ages of 6 and 10 years while adjusting for confounders.Maternal lipid levels in early pregnancy are positively associated with corresponding childhood lipid levels 6 and 10 years after pregnancy, independent of maternal body mass index and diet.Maternal lipid levels in early pregnancy may provide an insight to the lipid profile of children years later. Gestational lipid levels may therefore be used as an early predictor of children’s long-term health. Monitoring of these gestational lipid levels may give a window-of-opportunity to start early interventions to decrease offspring’s lipid levels and possibly diminish their cardiovascular risk later in life. Future studies are warranted to investigate the genetic contribution on maternal lipid levels in pregnancy and lipid levels of their offspring years later.The online version contains supplementary material available at 10.1186/s12884-022-04905-7. In pregnancy the maternal metabolism undergoes adaptations to support maternal and foetal demands. Regarding lipoprotein metabolism these changes consist of increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and in particular triglycerides during gestation . The preIt is known that maternal lifestyle factors, such as an unhealthy diet and obesity, are associated with an increased cardiovascular risk in children , 12. We This study was embedded in the Generation R Study, an ongoing population-based prospective cohort study from early pregnancy onward in Rotterdam, the Netherlands . Women eThe study has been approved by the Medical Ethical Committee of the Erasmus Medical Centre in Rotterdam (MEC-2007-413). For minors, written informed consent from a parent and/or legal guardian was obtained. From the rest of the participants written informed consent was obtained.Non-fasting blood samples were obtained at enrolment in early pregnancy  by trained research nurses to determine the levels of total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-c) . Total cPlacental syndrome was defined as having pre-eclampsia, a child born small-for-gestational age (SGA) or a spontaneous preterm birth (sPTB) in the index pregnancy. We obtained information on clinically diagnosed pre-eclampsia from medical records that were cross-checked with the original hospital charts . Pre-eclNon-fasting venous blood samples were collected to measure total cholesterol, triglycerides and HDL-c in the children at the age of 6 , and 10 years . Blood samples were obtained, transported, and stored as described in detail previously . Serum cP < .001]), and therefore, pre-pregnancy weight was used to calculate BMI in the analyses. At the age of 6 and 10 years, weight and height were measured without shoes and heavy clothing. We calculated BMI, and categorized children into age- and sex specific groups; normal-weight, overweight and obese, using the definition of Cole et al. [Information on maternal characteristics during pregnancy including age, ethnicity, educational level, parity, smoking, and the use of cholesterol or glucose regulating medication, and information on smoking and gravidity 6 and 10 years after pregnancy was obtained through questionnaires. We obtained information on pre-pregnancy weight through questionnaires at study enrolment. Maternal weight (kilograms) and height (centimetres) were measured at enrolment in early pregnancy and 6 and 10 years after pregnancy without shoes and heavy clothing, after which body mass index (BMI) was calculated (kilograms per square meter). Pre-pregnancy weight and measured weight at enrolment were highly correlated  for all lipid levels [First, we describe pregnancy and follow-up characteristics for all women and children. The mean ± standard deviation is presented for data with a normal distribution and the median with 90% range for data with a skewed distribution. Second, we examined the distribution of early pregnancy lipid levels in women, and in their children at the age of 6 and 10 years. Third, we present the lipid distributions in children stratified on child’s sex. Paired sample d levels . We testd levels . In thisd levels . Eight, 2 and 26.6% of the women smoked during their pregnancy. At the age of 6 years  children’s BMI was 15.9  and at the age of 10 years  children’s BMI was 16.9 .This study included 2692 mothers with lipids measured in early pregnancy and children with lipids measured at 6 years. Ten years after pregnancy, lipid measurements were available in 1673 children  ; while interestingly, paternal LDL-c was not associated with the offspring LDL-c . A studyGestational lipids in early pregnancy may be associated with childhood lipids through four potential pathways. First, we hypothesized that lifestyle factors would largely explain the association between gestational lipid levels and lipid levels of children years later. However, the associations between maternal and offspring total cholesterol, triglycerides, LDL-c, HDL-c, remnant cholesterol and non-HDL-c remained significant after adjustment for maternal pre-pregnancy BMI and diet. This suggests that lipid levels may have a certain level of stability; independent of these factors. Therefore, the second pathway we hypothesized on was that genetic inheritance is an important contributor to the association of gestational lipid levels with lipid levels in childhood. In healthy women, LDL-c levels above the 99th percentile have been found to be caused by unfavorable genotypes or mutations causing familiar hypercholesterolemia . In addiThis study found that girls had a more atherogenic lipid profile than boys, which is in agreement with a large population-based cohort providing reference levels for lipids in children . NotablyIncreased levels of total cholesterol, triglycerides, LDL-c, non-HDL-c, and low HDL-c levels are associated with cardiovascular disease and mortality later in life . In ordeCurrent guidelines of the American Heart Association and guidelines of the European Heart Association do not recommend to measure lipid levels in early pregnancy , 55. HowWe had a prospective data collection from early pregnancy onwards and a large sample of 2695 women and children with lipid measurements 6 years after pregnancy, and additional lipid measurements of 1673 children at the age of 10 years. Having two time points of lipid measurements during childhood is unique. In addition to the traditional lipid levels, we also assessed non-HDL-c and remnant cholesterol measures in children, since remnant cholesterol and non-HDL-c have already been proven important risk factors of cardiovascular disease in adults , 59. BloThe gestational lipid profile in early pregnancy is associated with the lipid profile of children years after pregnancy, independent of maternal BMI and diet. Monitoring of these gestational lipid levels may give a window-of-opportunity to start early interventions to decrease offspring’s lipid levels and possibly diminish their cardiovascular risk later in life.Additional file 1: Table S1. E-value of the association of maternal lipid profile in early pregnancy with their corresponding offspring lipid level at the age of 6 and 10 years. Table S2. Lipid profile in boys and girls 6 (n = 2692) and 10 years after pregnancy (n = 1673). Table S3. Association of maternal lipid profile in early pregnancy with their corresponding offspring lipid level at the age of 6 and 10 years in women without a placental syndrome in their index pregnancy. Table S4. Association of cut-off values of the maternal lipid profile in early pregnancy with their corresponding offspring lipid level at the age of 6 and 10 years.Additional file 2. STROBE statement.


The Coronavirus Disease 2019 (COVID-19) pandemic has spread across the world and resulted in over 5 million deaths to date, as well as countless lockdowns, disruptions to daily life, and extended period of social distancing and isolation. The impacts on youth in particular are astounding, with shifts in learning platforms, limited social outlets, and prolonged uncertainty about the future. Surveys have shown that mental health among youth has severely suffered during the pandemic. However, limited research to date has reported on physiological indices of stress surrounding the pandemic, such as cortisol. Cortisol is a stress hormone that typically increases during stressful situations and can have deleterious effects on mental and physical health when chronically heightened. The present study leveraged hair cortisol concentration measurements, which allowed the retrospectiveinvestigation of circulating cortisol prior to- versus after pandemic-related local lockdowns during the first wave of the pandemic. A final sample of 44 youth ages 10- to 18-years-old provided hair samples and reported on their perceived affective well-being and level of concern regarding pandemic-related stressors between May and June of 2020. We found significant levels of concern and decreases in affective well-being following local lockdowns. Moreover, we saw that cortisol robustly increased following local lockdowns, and those increases were predictive of changes in affect. These findings provide critical insights into the underlying neuroendocrinology of stress during the pandemic and support the need for resources to support youths’ mental health and well-being during this globally significant event.The online version contains supplementary material available at 10.1007/s10802-022-00967-5. The gravity of the situation during the first wave forced intermittent, sometimes prolonged school closures across the country , both of which are highly time-sensitive and can rapidly change over the course of just a few minutes. Thus, to accurately measure, one would have to anticipate that the event was coming and take measurements immediately before and after. However, researchers have more recently begun to leverage the strength of measuring hair cortisol concentrations (HCC), as hair samples reliably encapsulate mean cortisol levels over time  changes in affect and HCC are correlated, 2) changes in affect predict changes in HCC, and 3) changes in HCC predict changes in affect.M = 15.02 years, SD = 2.02; 25 males) were enrolled in this sub-study probing the psychological repercussions of the COVID-19 pandemic. The study was completed between May 10, 2020 and June 20, 2020. Participants’ parents electronically signed informed consent forms for the sub-study, and youth participants electronically signed assent forms following a complete description of the protocol. All procedures were approved by the University of Nebraska Medical Center’s Institutional Review Board and met ethical standards in accordance with the Declaration of Helsinki.Children and adolescents who were enrolled in ongoing longitudinal studies of brain and cognitive development in youth , and youth whose hair samples were less than 4 cm in length (n = 7) were excluded from analyses. For the purposes of this study, we focused on the most proximal  and the most distal  hair segments to capture changes in cortisol concentrations prior to- versus post-lockdowns. Details on collection and assays are provided in Parents were provided instructions for collecting hair samples and returning them by mail. All hair samples were taken between May 10, 2020 and June 20, 2020. Youth who declined to provide a hair sample  who completed all measures between May 10, 2020 and June 18, 2020. Given the dates of hair sample collection, coupled with an average growth rate of 1 cm per month, the most distal segment of hair captured approximately mid-January to mid-February of 2020. This timeframe approximately spanned the one-to-two months prior to the onset of local lockdowns (see next section). Complete demographics are detailed in Forty-seven youth had complete HCC and questionnaire data. Two youth had excessively high HCC measures, and one youth had an excessively high pre-lockdown negative affect score . Thus, the final sample was comprised of 44 youth age 10- to 18-years-old . By mid-February, the U.S. government had declared a public health emergency, and Omaha became a host site for treating American evacuees from abroad who were infected with the disease. Nebraska saw its first positive COVID-19 case outside of the biocontainment center on March 6 amid reports of panic shopping and empty store shelves. Over the following week, the World Health Organization declared COVID-19 a pandemic (March 11), the U.S. declared COVID-19 a national emergency (March 13), and public schools in the Omaha area closed their doors (March 13–19). Local stores, restaurants, childcare facilities, and recreational areas were mandated to close shortly thereafter. Unemployment claims skyrocketed almost overnight. Tensions in the local community rose over the next month (April) as governing officials sent mixed messages and began lifting restrictions. Several nearby cities became hotspots for COVID-19 due to working conditions , but employees were forced to continue working or risk termination. The Omaha city mayor mandated that city parks be closed only two weeks before the state governor announced plans to walk back restrictions on stores and restaurants. In early May, Omaha businesses began reopening at limited capacity with masking and social distancing guidelines. Over the next few weeks, restrictions continued to ease and Omaha hospitals reported all-time high numbers of COVID-19 patients. Nebraska saw its first cases of multisystem inflammatory syndrome in children, a condition impacting youths who were previously infected with COVID-19, in early June. For more, see Ryan .M = 7.73 stressors, SD = 3.70). Over one-third of the sample (36.36%) rated at least one stressor as concerning them “a lot” or “a great deal” . Descriptive statistics for each item are reported in Table “I'm worried that I could cause someone to get sick, and have to live with the guilt. Worry about friendships disintegrating. Worry that life will NEVER return to normal, worry that I'll never get a hug again.” – age 14“that this will continue for a lot longer than we expected and it will change the course of my life” – age 15“I missed graduation, I haven't seen my friends or talked to them at all and babysitting my brothers is terrible.” – age 14“If it's ever gonna end, what it's gonna be like when and if it ends.” – age 12Overall, 97.73% of youth in the present study indicated that at least one pandemic- or lockdown-specific stressor was concerning them in the past seven-days (t(46) = -2.85, p = 0.007) and negative affect (t(46) = -2.15, p = 0.04) increased between pre- and post-lockdown periods, whereas positive affect did not significantly change (t(46) = 0.66, p = 0.51). We report additional exploratory follow-up analyses probing changes in affect related to pandemic-specific stressors in Characteristics of included participants’ hair types and hair treatments are reported in p < 0.001), suggesting that those who had high cortisol to begin with saw less robust increases (or possibly saw decreases) following lockdowns. Additionally, older youth tended to have greater increases in cortisol from pre- to post-lockdown periods . There was no significant association with sex.The correlational model results are shown in Fig. p < 0.001). Interestingly, there was no significant association between retrospectively-reported pre-lockdown negative affect and the degree of change in negative affect . Neither age nor sex was significantly associated with the latent change in affect scores. There were no significant cross-domain predictions in the model.Looking at perceived affect assessed by the PANAS-C, the latent change in positive affect was negatively associated with pre-lockdown scores, such that youth who retrospectively reported higher positive affect prior to lockdowns tended to have greater decreases in positive affect following lockdowns . The association between changes in cortisol and changes in positive affect was trending toward significance . These data suggest that youth with greater increases in HCC tended to report greater increases in negative affect from pre- to post-lockdown and trended toward reporting greater decreases in positive affect from pre- to post-lockdown. Finally, the latent change in negative affect was also associated with the change in positive affect . Thus, youth who tended to have greater increases in negative affect also tended to have greater decreases in positive affect.Finally, correlations among the latent change scores showed that changes in HCC were significantly associated with changes in negative affect , suggesting that youth with greater increases in negative affect tended to see greater decreases in positive affect. Interestingly, neither of the predictions from latent change in affect scores to latent change in cortisol was significant (p’s = 0.15 and 0.63).The model in which latent changes in affect scores predicted the latent change in HCC had excellent fit, though the change in AIC and BIC relative to the correlational model was minimal Table . The conp = 0.034) and negative affect . Thus, in this model, the data suggested that youth who had higher HCC pre-lockdown tended to have greater decreases in positive affect, and greater increases in negative affect from pre- to post-lockdown. Additionally, we detected a significant association between age and the latent change in positive affect , with older youth tending to report less of a decrease in positive affect over time relative to younger participants. Importantly, changes in HCC were robustly predictive of both changes in positive affect  and changes in negative affect . The data suggest that youths who showed greater increases in cortisol over time tended to report greater increases in negative affect, and greater decreases in positive affect.Our final model examined whether latent change in cortisol could predict latent changes in positive and negative affect. Again, the model had excellent fit, and showed minimal change in fit compared to the correlational model Table . Conclusnot predict changes in HCC. We further discuss these findings and their implications below.The present study examined the extent to which physiological stress responses and mood changed during the COVID-19 pandemic in typically-developing children and adolescents. As expected, youth reported significant increases in negative affect after lockdowns began. Contrary to our hypothesis, there was no significant shift in positive affect overall, though we did see an effect in youth who reported greater levels of recent concern over pandemic-related stressors. Additionally, we saw significant increases in mean HCC following local lockdowns, suggesting robust physiological stress responses surrounding the pandemic. Our key finding was that changes in HCC robustly predicted perceived changes in mood. Notably, changes in mood did The greatest strength of this study was the measurement of HCC prior to and after local lockdowns began. By using HCC, we were able to reliably index shifts in circulating cortisol levels among youth surrounding a pivotal, high-stress period of the COVID-19 pandemic. As expected, we saw robust increases in HCC following local pandemic-related lockdowns. Moreover, the degree of change in circulating cortisol was dependent on baseline levels, such that youth who had higher HCC prior to lockdowns tended to show smaller increases in circulating cortisol than youth with lower baseline HCC. Our findings were well-aligned with the extant literature showing increases in cortisol following a major stressful event , unpredictability and uncertainty surrounding the progression and duration of the global spread , and psychological distress and disruptions to daily life due to lockdowns  versus the social self  have very different presentations  samples to estimate properly  study Below is the link to the electronic supplementary material.


Outreach, including patient navigation, has been shown to increase the uptake of colorectal cancer (CRC) screening in underserved populations. This analysis evaluates the cost-effectiveness of triennial multi-target stool DNA (mt-sDNA) versus outreach, with or without a mailed annual fecal immunochemical test (FIT), in a Medicaid population. A microsimulation model estimated the incremental cost-effectiveness ratio using quality-adjusted life years (QALY), direct costs, and clinical outcomes in a cohort of Medicaid beneficiaries aged 50–64 years, over a lifetime time horizon. The base case model explored scenarios of either 100% adherence or real-world reported adherence  with or without real-world adherence for follow-up colonoscopy . Costs and outcomes were discounted at 3.0%. At 100% adherence to both screening tests and follow-up colonoscopy, mt-sDNA costed more and was less effective compared with outreach with or without FIT. When real-world adherence rates were considered for screening strategies (with 100% adherence for follow-up colonoscopy), mt-sDNA resulted in the greatest reduction in incidence and mortality from CRC  compared with outreach with or without FIT; mt-sDNA also was cost-effective versus outreach with and without FIT . mt-sDNA remained cost-effective versus FIT, with or without outreach, under real-world adherence rates for follow-up colonoscopy. Outreach or navigation interventions, with associated real-world adherence rates to screening tests, should be considered when evaluating the cost-effectiveness of CRC screening strategies in underserved populations. Although the prevalence of up-to-date screening with any recommended test among individuals aged 50 years and older has increased over time,2 reducing the risk of death from CRC requires repeat screening for individuals with normal test results and additional evaluation through follow-up colonoscopy of individuals with abnormal test results.3 Inequalities in uptake of screening exist and differences in access, use, and quality of screening may contribute to disparities in CRC death rates.4Colorectal cancer (CRC) is the second most common cause of cancer deaths; screening can reduce both the incidence of and death from CRC.5 Delays or failures in completing a follow-up colonoscopy have been associated with an increased risk of CRC diagnosis and mortality.6 Although provider-related (a lack of recommendation for screening) and patient-related barriers  may impede screening,4 these barriers may be exacerbated in underserved populations, such as Medicaid enrollees.7 Outreach interventions, including patient navigation or reminders, may address these barriers by either facilitating the screening process or engaging patients and providers to increase adherence.8Optimizing the quality of CRC screening depends on increasing the uptake of and follow-up to all aspects of the CRC screening continuum, from completion of initial tests to follow-up colonoscopy.9 However, noninvasive screening alternatives, such as FIT and mt-sDNA, can be done at home and do not require the restriction of either diet or medication, nor cathartic preparation10; these options may increase the accessibility and uptake of screening. Furthermore, mt-sDNA incorporates patient navigation to facilitate completion within its test. Although FIT does not inherently include outreach, programs and practices may choose to incorporate their own outreach strategy when providing FIT as an option to increase adherence. This analysis evaluates the cost-effectiveness of noninvasive CRC screening modalities of mt-sDNA versus outreach, with and without FIT, in a simulated Medicaid population.All guideline-recommended CRC screening alternatives have been demonstrated to be cost-effective compared with no screening.11 Details of this CRC-AIM model have been published previously12 and demonstrate substantial cross-model validity to the other Cancer Intervention and Surveillance Modeling Network model (CISNET).11The Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model (CRC-AIM) models the natural sequence of adenoma detection to carcinoma progression in unscreened patients, and includes test-related attributes, such as patient adherence to the initial screening strategy and follow-up colonoscopy.13 Complications included in the model are serious gastrointestinal events, other gastrointestinal events, and cardiovascular events, in line with CISNET methodology.14In brief, adenomas may grow and transition to preclinical cancer, which may transition to symptomatic CRC. CRC screening facilitates the identification and removal of adenomas and potential early detection of preclinical CRC. The ability of a stool-based CRC screening test to detect an adenoma or preclinical CRC is dependent on test performance  and test completion . All patients with a positive noninvasive screening test undergo a follow-up colonoscopy. Patients with a history of adenomas of any size are assumed to undergo surveillance with colonoscopy; time to next surveillance colonoscopy is based on the latest recommendations for follow-up colonoscopy.15 For annual FIT screening, outreach strategies vary across practices.This model focuses on estimating the cost-effectiveness of triennial mt-sDNA and annual FIT, both of which are guideline-endorsed stool-based CRC screening strategies. Although an annual guaiac-based fecal occult blood test is also a guideline-endorsed stool-based screening strategy, it was not included in this analysis because of its lower test performance parameters compared with both FIT and mt-sDNA. All mt-sDNA orders include centralized patient navigation support .16 The estimates of sensitivity and specificity for mt-sDNA and FIT screening are identical to those applied in previous CISNET modeling analyses, which were used to inform the 2016 USPSTF guideline recommendations and are presented by adenoma size and cancer stage in 14Therefore, two previously reported outreach scenarios were modeled: a mailed letter encouraging CRC screening completion along with instructions about how to obtain a FIT test , and outreach through a mailed letter encouraging CRC screening completion along with a FIT test.17This analysis is from the perspective of the Medicaid payer and assumes a cohort of 1 million patients aged 50–64 years, alive and free of clinically diagnosed CRC. Upon entry into Medicaid, all patients are considered eligible for regular screening. The model uses a lifetime time horizon; all costs and outcomes were discounted at 3.0%.18 Screening costs for outreach with FIT and FIT itself were obtained from a study that evaluated the cost-effectiveness of a mailed outreach letter with a FIT test in a Medicaid population.19 The cost of FIT from this source is consistent with the cost of FIT from the Centers for Medicare & Medicaid Services Clinical Laboratory Fee Schedule.This model only considers direct medical costs . The cos19 given that program costs vary across jurisdictions and by type of outreach. The screening cost associated with colonoscopy was taken from a claims database study20; the cost of complications were sourced from a budget impact and cost-consequence study.21 CRC-related direct medical costs were stratified by stage and time since diagnosis.22 Costs are reported in 2021 US dollars and were inflated using the Medicaid-to-Medicare Fee Index.23The screening cost of an outreach alone was assumed conservatively to be equivalent to the cost of a FIT test,24 Utility decrements for all colonoscopies and complications for colonoscopy also were incorporated.25 Utility loss was included for patients who get CRC and was stratified by both level of care stage of CRC stage (Stage I–III and Stage IV); these were applied on a per-patient per-year basis.25Utility inputs at baseline, adjusted for age, were based on EuroQoL-5D US population norms .24 Utili12; therefore, 3 different sets of adherence rates were considered in these analyses. In Analysis 1, it was assumed that patients were 100% adherent to both stool-based screening and follow-up colonoscopy.Adherence to screening strategies and follow-up colonoscopy impacts the cost-effectiveness of screening strategiesAnalysis 2 uses real-world screening estimates for stool-based screening strategies and assumes 100% adherence to follow-up colonoscopy .n = 26,132) who, once determined eligible for screening by mt-sDNA, had a test ordered directly by their provider that was then shipped to the order-specified address by Exact Sciences Laboratories.26 Reported real-world adherence rates for outreach with or without FIT were taken from a randomized controlled trial assessing adherence among Medicaid beneficiaries (n = 2144).16Reported real-world adherence rates for mt-sDNA were taken from a cross-sectional study where adherence to mt-sDNA was assessed among Medicaid beneficiaries  of mt-sDNA versus outreach with or without FIT was the primary outcome. Secondary outcomes include clinical outcomes (either benefits or harms of CRC screening) and are presented as totals over the model lifetime per 1000 patients. Total lifetime CRC screening costs  are presented along with quality-adjusted life years (QALYs). There is no official willingness-to-pay (WTP) threshold in the United States; however, ICERs <$100,000 per QALY are considered to provide good value.Across the 3 base case models , patients were assumed to have fixed cross-sectional adherence rates over time. Furthermore, patients who were nonadherent to follow-up colonoscopy were assumed to be nonadherent until they became symptomatic. Two alternate scenarios to these assumptions were explored.28 Considering a base case of 38% adherence for colonoscopies in a given year,29 noncompliant individuals are offered screening every year at a constant declining rate (r) to ensure that these individuals remain noncompliant: 38% × (1 − r)t, if colonoscopy is delayed by t years, where 0 ≤ t ≤ 10. The result is a capped adherence rate where simulated individuals who are compliant with CRC screening match the reported NHIS rate (62.4%).30 The derived calibration factor is applied to all stool-based screening strategies to simulate a capped adherence scenario approach for Analysis 2 and 3.Data from the National Health Interview Survey (NHIS) suggests that up to 62.4% of individuals are up-to-date for CRC screening. A scenario analysis was explored using a calibration factor to reflect the fact that overall adherence to colonoscopy over 10 years may not reach 100%.In the base case models, patients who were nonadherent to follow-up colonoscopy were assumed to remain nonadherent until symptomatic. Scenario analyses were explored in which patients who did not undergo their follow-up colonoscopy initially were offered the follow-up colonoscopy in the following year, before being considered nonadherent. This scenario was explored for Analysis 3 under both the base case scenario and the capped adherence over time scenario.Sensitivity analyses were undertaken to account for uncertainty around model parameters and to test the robustness of the models. One-way sensitivity analyses for Analysis 3 in the base case were conducted varying adherence inputs 20% and costs and utility inputs ±10% from their base case value. A probabilistic sensitivity analysis also was conducted, in which all parameters are varied simultaneously at the same rates as the 1-way sensitivity analysis.26 21.1% for outreach + FIT,16 and 12.3% for outreach alone,16 whereas adherence to follow-up colonoscopy was varied from 0% to 100%.Threshold analyses were undertaken to evaluate the incremental cost-effectiveness of mt-sDNA versus outreach with or without FIT across various adherence rates. The threshold analyses presented the ICER for 2 different scenarios. In the first scenario, screening test adherence rates were varied from 0% to 100% and adherence to follow-up colonoscopy was held constant at 100%. In the second scenario, adherence to the screening test was held constant at 51.3% for mt-sDNA,When 100% adherence is assumed for both the screening test and follow-up colonoscopy , outreach with or without FIT results in greater reductions in incidence (51.9% for both) and mortality (57.0% for both) compared with mt-sDNA  . When reDiscounted total costs and QALYs are presented in When screening rates over time are capped, the ICER for mt-sDNA versus outreach + FIT decreases to $15,561  and $27,306 , representing greater cost-effectiveness. Similar results are observed for mt-sDNA versus outreach alone: the ICER decreases to $14,128  and $25,154 . When patients are given an additional year to be considered adherent to follow-up colonoscopy, the ICER for mt-sDNA versus outreach + FIT using the inputs for Analysis 3 is $36,274 in the base case and $19,227 in the capped adherence scenario. Similar results are observed for mt-sDNA versus outreach alone: using the inputs for Analysis 3, giving patients an additional year to be considered adherent results in an ICER of $26,515 for the base case and $17,053 for the capped adherence scenario.One-way sensitivity analyses for mt-sDNA versus outreach (with or without FIT) found that adherence to follow-up colonoscopy across screening strategies had the largest impact on the ICER when real-world reported adherence rates were considered   and S3.26 and 21.1% for outreach + FIT16), and the adherence to follow-up colonoscopy is varied from 0% and 100%. At an adherence rate of 66.7% to follow-up colonoscopy for mt-sDNA , screening adherence to outreach + FIT would need to exceed 85% to be cost-effective versus mt-sDNA at a WTP of $100,000/QALY (with fixed screening adherence rates).Similar results were found in the comparison of mt-sDNA with outreach alone , B.In the probabilistic sensitivity analysis, mt-sDNA was cost-effective over outreach with or without FIT in 100% of the simulations at a WTP threshold of $100,000/QALY .8 These results highlight the importance of outreach in increasing adherence and the associated impact on cost-effectiveness in an underserved population of Medicaid beneficiaries. At reported real-world rates of adherence, mt-sDNA is cost-effective compared with outreach through an outreach letter with or without FIT. Furthermore, mt-sDNA remains cost-effective when exploring alternate adherence rates across a wide range of assumptions. Programs can use these cost-effectiveness results to evaluate the impact of different screening tests and differing levels of adherence on CRC screening outcomes.For CRC screening, a common perspective is “the best test is the test that gets done.”31 Unlike FIT, patient navigation through to completion of the screening test is integrated with every mt-sDNA test: patients are able to engage with the patient navigation system at all hours through telephone, kits are shipped directly to their home, and the kit includes a prepaid shipping label.15 Although adherence rates were higher when FIT was provided with an outreach letter than for an outreach letter alone, adherence to outreach + FIT would need to exceed 40% to be cost-effective versus mt-sDNA at adherence rates of 51.3%.The study results are similar to others that have explored the cost-effectiveness of outreach strategies in CRC screening for underserved patients. A previous microsimulation model of Medicaid enrollees found that patient navigation had a greater impact on overall screening adherence rates compared to reminders alone or mailed FIT with a reminder.32 However, the absolute increase in screening associated with these interventions is variable. A randomized controlled trial that explored different forms of reminders for increasing adherence to FIT found that reminders included with a live call were more effective than written communication only; however, the estimated overall return rate of FIT remained <35% after the delivery of reminders.33Multiple outreach strategies exist to increase adherence to CRC screening, including invitations from providers, reminder letters, telephone calls, and text messages, or reaching participants during other health care interactions.34 Further assessment of the reproducibility in an underserved population and scalability of this locally provided labor-intensive approach is needed before adoption as a broadly applicable strategy. Other interventions with FIT were found to be less effective in increasing screening rates. Among an underserved population composed largely of Medicaid beneficiaries, a randomized controlled trial of a text message only versus an opt-out option of receiving a FIT kit resulted in screening rates of 19.6%,35 whereas a separate randomized controlled trial comparing a text messaging and lottery incentive resulted in screening rates of 12.1%.36More encouragingly, a recent study found that when dual Medicaid/Medicare enrollees are first called to see if they would like to be mailed a FIT test, the completion rate among those who expressed interest was 68%.37 The differences in the success of interventions to increase screening may be explained by multiple factors. O'Connor et al examined sociodemographic and health-related factors that moderate the effect of mailed FIT kit outreach in a cluster-randomized pragmatic trial in a primarily low-income population.38 While FIT completion was higher in the intervention group, compared with the control group, the only moderator with a statistically significant interaction was race, with persons of Asian descent having a 2-fold response to the intervention.38 The authors speculated that this may have been because of the wordless FIT instructions developed for the trial.39 This universal outreach may explain some of the success of mt-sDNA in a variety of populations: the patient navigation integrated within mt-sDNA is currently available in >240 languages.15A systematic review found that various interventions increased median FIT participation between 3.1% and 21.5%.40Data from this study analyses should be interpreted in the context of the assumptions. Although the screening test adherence inputs used in this model are based on real-world data, these data are based on a limited number of studies. However, the threshold analyses conducted allow cost-effectiveness end points to be correlated with a range of potential adherence rates. As no data were available for follow-up colonoscopy in patients who received mt-sDNA, a conservative assumption of equal adherence to follow-up colonoscopy was used; data in other populations indicate that follow-up to colonoscopy is higher among patients with a positive mt-sDNA than those with a positive FIT.Higher rates of FIT adherence have been observed in combination with outreach programs in non-Medicaid populations; these alternate adherence values and their impact on cost-effectiveness can be explored through this study's threshold analysis. Although a proxy cost of a FIT test was used for the outreach alone comparator, the cost used is conservative; an outreach strategy in clinical practice likely will cost more, which would increase the cost-effectiveness results herein. This model focused on noninvasive stool tests; however, barriers to completion of a test may be different for invasive tests such as colonoscopy.This article did not explore factors associated with adherence; further study is needed to better understand the role of patient characteristics and preference on screening adherence behavior. Furthermore, although this article explores both cross-sectional and longitudinal adherence through the base case and scenario analyses, the impact of intermittent adherence on the cost-effectiveness of screening strategies should be analyzed in detail in future models.3 Patient navigation or outreach interventions may increase adherence rates to screening tests. These interventions should be considered when evaluating the cost-effectiveness of CRC screening strategies to ensure that underserved populations have the best chance of achieving and maintaining adherence to screening, allowing the maximum clinical benefit of reduced incidence of and mortality from CRC.Being adherent to screening may reduce the risk of dying from CRC by >60% and increasing adherence to CRC screening strategies remains a key public health goal.