APOE rs7412 against SARS-CoV-2 infection  after correction for multiple comparisons. This protective effect was also ascribed to the APOɛ2 allele . The genetic variant rs7412 resulting in ApoE2, genetic determinant of lipid and lipoprotein levels, could play a significant role protecting against SARS-CoV-2 infection.The pandemic burden caused by the SARS-CoV-2 coronavirus constitutes a global public health emergency. Increasing understanding about predisposing factors to infection and severity is now a priority. Genetic, metabolic, and environmental factors can play a crucial role in the course and clinical outcome of COVID-19. We aimed to investigate the putative relationship between genetic factors associated to obesity, metabolism and lifestyle, and the presence and severity of SARS-CoV-2 infection. A total of 249 volunteers  characterized for dietary, lifestyle habits and anthropometry, were studied for presence and severity of COVID-19 infection, and genotyped for 26 genetic variants related to obesity, lipid profile, inflammation, and biorhythm patterns. A statistically significant association was found concerning a protective effect of  Impaired immune response or exacerbated pro-inflammatory response are associated to the main complications of people affected of COVID-19. In addition, emerging evidence demonstrates close link between metabolism and the viral disease process2.COVID-19 pandemic that we are currently experiencing caused by SARS-CoV-2 has affected nearly 350 million people and caused almost 5.6 million deaths globally as of January 20225.The clinical course of COVID-19 is highly variable. Elderly or patients with some comorbidities such as diabetes mellitus, hypertension, renal dysfunction, cardiovascular diseases (CVDs) and cancer are the most vulnerable groups to suffer severe or fatal cases due to this infection6.Effective control of metabolic parameters  might represent a successful approach to dealing with the acute effects of infection by decreasing virus entry into cells and reducing local inflammatory response. Studies have also shown that the nutritional status  of old patients with COVID-19 has a significant impact on their clinical outcomes8. The metabolic variability among individuals in the response to diet should be taken into consideration to individualize healthy eating advice, which will promote a reduction in the risk of non-communicable diseases (NCDs). Genetic factors are unmodifiable, but their effects can be modulated through lifestyle and environmental factors6.Recently, the importance of genotype-environment interactions in shaping the different metabolic phenotypes has been stressed, where diet, exercise, circadian rhythms and gut microbiome appear as the most important environmental factors11. These studies disclose a severe deregulation of lipoproteins leading to increased triglycerides (TG), together with an alteration of lipoprotein particle levels and an increase in VLDL subclasses with intermediate size9. In turn, other studies showed that COVID-19 adult patients presented lower levels of high-density lipoprotein (HDL-C), which was correlated with a higher risk of developing severe events. In addition, increased TG/HDL-C ratio was associated with disease severity and mortality in COVID-19 patients11. Therefore, the current state of research reflects a promising scenario for the discovery of useful metabolism-markers for the early identification of patients at high risk of infection and serious diagnosis.COVID-19’s aetiology (its cause or set of causes), beyond SARS-CoV-2 infection, is currently the subject of a large research effort worldwide, given that the disease, at least in its more severe manifestations, occurs through a host huge inflammatory reaction. In this way, several studies have suggested associations between the lipid profile and the infection status or severity of this disease13. Although the knowledge concerning the mechanisms of interaction at a molecular level of the biological clock and viral infections is still scarce, it is known that viruses are likely to alter the biological processes of infected cells in order to promote their replication and to spread to various tissues. Possible deregulations of circadian rhythms could have a substantial impact on the severity of the symptoms14.Likewise, an involvement of circadian rhythms regarding the regulation of the immune system as well as in the severity of infections has been observed15.In this perspective, Precision Nutrition is a complementary therapeutic strategy in the management of metabolic and immune alterations associated to COVID-19 poor prognosis. Personalized nutrition combines different aspects to obtain a holistic view of the individual, such as nutrigenetics, detailed phenotyping, and a big set of data obtained from omics technologies . Importantly, nutritional interventions based on omics knowledge represents an effective tool to fight against infections and chronic conditions. Hence, Precision Nutrition should also be considered as a complementary tool within the COVID-19 pandemicAPOE gene is associated to diminished susceptibility to SARSCoV-2 infection.Although COVID-19 is not primarily a metabolic disease, proper control of some metabolic parameters such as glycemia, blood pressure and lipid levels represent a key therapeutic approach to prevent and ameliorate the acute effects of this viral infection. Within the framework of Precision Nutrition, herein we have analyzed 26 genetic variants in metabolic genes related to obesity, inflammation, chronobiology and nutrient sensing to evaluate their putative associations to the susceptibility and evolution of symptomatology to SARS- CoV2 infection. We identify minor allele rs7412 polymorphism in A study to identify single nucleotide genetic polymorphisms involved in the SARS-CoV-2 infection was conducted in the GENYAL population. A total of 371 volunteers from this cohort answered the COVID-19 questionnaire designed for this study. COVID-19 questionnaire plus genotyping data were finally restricted to a total of 249 subjects with enough reliable data  presented in Table vs “not clear” vs “infected”). Figure p values (before and after Bonferroni correction for multiple tests) obtained for each of the SNPs in these models.The objective of this study was to identify putative associations between SARS-CoV-2 infection and genetic factors involved in metabolic or inflammation processes. In this way, 26 SNPs corresponding to genes related to lipid metabolism, obesity, inflammation, and biorhythms were tested for their association with SARS-CoV-2 infection and severity. The frequencies obtained were similar to the European frequencies and the Hardy Weinberg equilibrium was calculated as shown in Table APOE rs7412 and SARS-CoV-2 infection status was found after adjusting for multiple testing corrections. For the additive model, a higher protective effect for each T allele was found with respect to SARS-CoV-2 infection , which is present in the minor ɛ2 allele of APOE. Also, for the dominant model (CC vs CT + TT) the higher protective effect for the T allele  was found. These results are presented in Table A significant association between the genetic variant Figure APOE gene has three main alleles, ɛ2, ɛ3 and ɛ4, coding for three corresponding isoforms of apolipoprotein E: E2, E3 and e4, respectively. Table APOE genetic variant, the analysis of the genotypes performed showed a positive association between the risk of SARS-CoV-2 infection and CLOCK gene rs3749474 polymorphism (p = 0.024), although statistical significance was lost after Bonferroni correction  , suggesting a cooperative role of both genetic variants in relation to the infectivity of the virus.In view of these results, an interaction model between CLOCK gene on SARS-CoV2 infection, as well as the correlation that the two SNPs, APOE and CLOCK, have together regarding susceptibility to COVID-19 infection.This remarkable finding could be an initial indicator of the potential predictive value of polymorphic variants in the Finally, we investigated the possible modulating effects of diet or medication on SARS-CoV-2 infection. Healthy eating index (IAS), energy intake, total lipids and carbohydrates, simple sugars and saturated fatty acids consumption were tested, as well as consumption of anti-inflammatory, hypotensive or lipid lowering drugs for medication. No significant correlation with SARS-CoV-2 infection or symptoms severity was found in any case.The present work has focused on the study of genetic factors involved in SARS-CoV-2 infection and its severity in order to broaden the knowledge of the genetic influence on the probability of infection. To this end, single nucleotide genetic variants in genes related to lipid metabolism, inflammation and biorhythms have been analyzed.APOE rs7412 and the SARS-CoV-2 infection status was detected for the additive and dominant models, that remained significant after Bonferroni multiple-test correction. Both models suggest that the minor T allele (dominant model) or each copy of the T allele (additive model), would elicits a protective effect against SARS-CoV-2 infection. Nonetheless, given the cross-sectional nature of this study, it is not possible to fully demonstrate from here a causal involvement of the ε2 allele in the observed decrease in infection. However, the significant association reported in this work opens the door to future controlled longitudinal trials capable of confirming this hypothesis, of great interest given the need to understand the risk factors of COVID-19 disease.A statistically significant association between the genetic variant 21. Previous studies have evidenced the association of APOE alleles with susceptibility to infection by viruses, with elevated levels of lipoprotein(a) (Lp(a)), with local extracellular vesicle biogenesis in the brain, with the levels of the Willebrand factor and the modulation of angiotensin converting enzyme 2 (ACE2)27. These processes may be related to a prothrombotic condition which, together with the inflammatory character of SARS-CoV-2 infection, may lead to a higher infection capacity and severity. In addition, different isoforms of apolipoprotein E can give rise to multiple phenotypes, with numerous factors intervening in their biogenesis and expression regulation. For this reason, the multifaceted associations to APOE gene require multiple approaches to be taken into account20.This protective effect may be related to multiple processes where apolipoprotein E is implicated including cardiovascular function, immune system and inflammationAPOE alleles  in the population due to the multiallelic nature of apolipoprotein E gene. Nonetheless, the results of the present study revealed a protective effect of the minor T allele of the SNP rs7412 which is found only in the minor ɛ2 allele of APOE. Consequently, these results are complementary to those observed in other studies, where the ɛ4 allele increases the risk of SARS-CoV-2 infection and severity of COVID-19 the symptoms30.The knowledge provided in the current literature regarding COVID-19, refers mainly to 32. On one hand, studies have shown that the rs7412 genetic variant had the strongest association with LDL-TG and RLP-C as well as a significant association with increased TG and HDL-C levels, and with decreased LDL-TG, LDL-C, total cholesterol, non-HDL-C, and Lp(a) levels33. In addition, several studies have reported a significant association between the APOE2-determining allele of rs7412 and Lp(a) concentrations35. These investigations similarly revealed a decrease in Lp(a) in the population carrying the allele associated with rs741235. In the same time, elevated levels of this lipoprotein have been proposed to be associated with the risk of SARS-CoV-2 infection and with a very high risk of thrombosis23. Therefore, these mechanisms could help to explain the potential influence of this genetic variant on SARS-CoV-2 infection. For this reason, this study may help to provide new avenues for studying ApoE purposes, evaluating not only the effect exerted by ɛ4 but also the protective effect of rs7421 and ɛ2 allele against COVID-19.In addition, genome wide significant associations studies (GWAS) related to rs7412  and higher odds of surviving and longevity have been foundAPOE gene alleles and the risk of SARS-CoV-2 infection was assessed. As alleles ɛ2, ɛ3 and ɛ4 in APOE gene correspond to genotypes rs7412-T/rs429358-T; rs7412-C/rs429358-T; and rs7412-C/rs429358-C, respectively, we evaluated the combination of the two SNPs rs7412 and rs429358 in the risk of infection. In the resulting model, a protective effect was found only for ɛ2 allele after adjusting for the Bonferroni correction. These results, consequently, are in accordance with our hypothesis on the protective effect exerted by the ɛ2 allele. In the same time, published literature reports the beneficial character of apolipoprotein E2 according to cardiovascular diseases, neuroprotection, and other age-related disease traits and survival implicated in the promotion of longevity37. This way, a lower affinity for the LDL receptor, reduced hypertension and/or increased neuroprotective capacity are proposed mechanisms which may contribute to the protective mechanism against SARS-CoV-2 infection39. Therefore, the multifaceted nature of APOE pleomorphic gene, specifically the ɛ2 allele, may have a protective effect against COVID-19 disease.Subsequently, the effect of the 40. This seems to be due to the neurotropic character of the virus, where potential entry of the virus into the vascular endothelial cells of the brain is possible41. In this scenario, a possible neuroprotective effect could be also hypothesized by the rs7412 or the ɛ2 allele, given its beneficial character in relation to neurodegenerative mechanisms41.Besides that, as COVID-19 pandemic evolves, several discouraging long-term effects are being observed. These include neurological manifestations such as smell/taste disorders and non-specific and possibly systemic neuropathological symptomsDiet and medication do not seem to interfere with infection status and rs7412. However, more studies should be conducted in this direction. This study has been performed in a mainly non-pathological population and a larger sample size may be necessary for future analysis.42. Disruptions in circadian rhythms have been reported to affect both viral replication and dissemination within the host, as well as innate and adaptive immune responses, which can modulate the infective capacity of the virus and its clinical manifestations43. Regarding the infection by SARS-CoV-2, in addition to the previously mentioned, it has been reported that the circadian clock machinery is closely involved in the transcriptional expression of ACE2, the main responsible receptor for the viral entry of SARS-CoV-2 into the cells44. In view of the previous evidence, several authors accentuated the urgent need to study the potential contribution of circadian rhythms on COVID-19 disease to clarify whether this relationship can play a role in the spread of this pandemic47. In this sense, our study shows a positive association between the minor T allele of the rs3749474 variant of the CLOCK gene (a core component of the circadian clock) and the risk of infection by SARS-CoV-2 (p = 0.024), although this significance was lost after adjusting for Bonferroni correction, probably due to the low sample size. Despite the fact that the genotype frequencies of this polymorphism were similar to those described in the European population, infected subjects presented an increased incidence of TT + CT genotypes compared to non-infected subjects, pointing to a higher infection rate in the T allele carriers of this polymorphism. This experimental finding describes for the first time a potential direct relationship between a gene involved in the circadian clock and the modulation of SARS-CoV-2 infection, thus opening the door to future studies in this field.The immuno-inflammatory activation as a consequence of a viral infection is a complex system which is affected by multiple factors, including the host circadian clockCLOCK gene has also been associated with altered metabolic features. Subjects who carry the T allele of this variant show a higher energy intake16 BMI and risk of obesity48. After numerous clinical reports, it is a statement that obese patients, and especially those with a higher BMI, are severely affected by COVID-19 and present a worse outcome than patients with lower BMI51. Again, this supports the link described in our study between the rs3749474 polymorphism and SARS-CoV-2 infection.The rs3749474 polymorphism of the APOE and CLOCK polymorphisms have shown significant associations with SARS-CoV-2 infection, and their statistical significance is also enhanced when they are analyzed together in the same model. This suggests a cooperative role of both genes related to the infectivity of this virus. Other authors have previously described cases where the CLOCK gene and APOE genotypes can interact together modulating the progression of inflammatory-based diseases53. This reinforces the cooperative role proposed for these polymorphisms on the susceptibility to infection by SARS-CoV-2, as well as the progression and severity of other inflammatory-based diseases in which these genes may play a major role.It is noteworthy that of all the polymorphisms studied in our population, APOE and CLOCK could be involved in modulating the risk of SARS-CoV-2 infection as reported, but they may not have a major influence on the progress of the disease once established. However, our study has some limitations. In the first place, the sample size of the infected population might not be large enough to appreciate a significant influence of APOE and CLOCK in the severity of symptoms. Therefore, it would be advisable to test this association in a large number of infected subjects to ensure if these factors could affect the severity of symptoms caused by COVID-19 disease. Eventually, because of the complicated epidemiological situation Spain was suffering while the study was being performed, the limited availability of diagnostic tests, and the retrospective nature of the study, it was not possible to verify firmly the participants’ SARS-CoV-2 infection. Nonetheless, a validation and verification mechanism of past infection would have been interesting and will be considered in new investigations. Future studies with larger sample size are warranted to contrast the results obtained in this research. Additionally, analyzing these associations in an ethnically diverse population could be relevant as ethnicity has an impact on these variants.The relationship between the severity of the symptoms in the group of individuals infected by SARS-CoV-2 and the analyzed genetic polymorphisms was also assessed. However, no significance was noticed for any of the SNPs tested. These results could suggest that APOE rs7412 and the APOɛ2 allele, may confer a certain protection against SARS-CoV-2 infection. This observation will allow the performance of fully longitudinal studies to confirm this novel hypothesis from a causative point of view. In addition, the data here obtained and publicly shared will allow the estimation of appropriate sample sizes and power for these future trials.To conclude, although more studies need to be conducted to corroborate the current results, we observed than the minority allele (T) of the genetic variant Subjects that participated in this study were recruited through the Platform for Clinical Trials in Nutrition and Health (GENYAL), at IMDEA Food Institute . Given the novelty of the COVID pandemic, no information about the variability of the data to collect was available, precluding the use of sample size calculations, so we used the largest sample available. Volunteers included in the GENYAL database were contacted to participate in this study. A total of 371 volunteers of European ancestry were recruited with the objective to link data related to genetic variants, anthropometric measurements, dietary patterns and lifestyle with SARS-CoV-2 infection and severity of COVID-19 disease. Inclusion criteria were the following: previous participation in GENYAL Platform studies, adequate level to understand the research propose, agreement to voluntarily participate in the study and provide informed consent. Only those who refused to give their consent to participate in this study were excluded. CONSORT flow diagram is shown in Fig. This study was performed according to the guidelines present in the Declaration of Helsinki and all procedures involving human subjects were approved by the Research Ethics Committee of the IMDEA Food Foundation (CEI 27-666). Written informed consent to enroll in the study was obtained from all the participants. The trial registration number from ClinicalTrials.gov is NCT04067921.55. Body weight was assessed using the body composition monitor BF511 . Height was assessed using a stadiometer . Waist circumferences were measured using a Seca 201 non-elastic tape . The dietary patterns of each participant were assessed using a validated 72-h dietary food record and a food frequency questionnaire56. Energy intake, healthy eating index, macro and micronutrients from the dietary records were analyzed using the DIAL software . Regarding lifestyle data, physical activity parameters  and smoking habits (cigarettes/day) were collected from every participants57.Anthropometric measurements such as height, weight and waist circumference were measured following standard validated techniques59. Blood samples were obtained from study participants and stored at − 80 °C until DNA extraction. Genomic DNA from each participant was isolated using the QIAamp DNA Blood Mini Kit . DNA concentration and quality were assured in a nanodrop ND-2000 spectrophotometer . Gene genotyping was performed using TaqMan OpenArray plates with the QuantStudio™ 12 K Flex Real-Time PCR System  according to the manufacturer’s instructions60. The results obtained were analyzed with the TaqMan Genotyper software61. Duplicates of the samples were made, obtaining more than 99% of technically valid genotypes.Single nucleotide polymorphisms related to lipid metabolism, obesity, circadian rhythm, immune system, and estrogens were previously screened and selected according to previously published proceduresDegree of exposure to SARS-CoV-2 Low (Constant home confinement + No contact with people infected by COVID-19), Medium (Rest of participants), High (Coexistence with a person infected by COVID-19/No adherence to COVID-19 security guidelines/Participants with possible exposure to COVID-19 at work).Diagnosis of the disease Not infected , Not clear (Possible infection but no diagnostic test was performed), Infected by SARS-CoV-2 .Symptomatology and severity (Table ) Null (No symptoms/Symptoms described by participant as chronic and not associated with COVID-19), Mild-moderate (Mild and moderate symptoms 1–3 weeks/Mild symptoms > 3 weeks/Severe symptoms ≤ 1 week), Severe .Associated risk factors Low (0 risk groups), Medium (1 risk group), High (> 1 risk group). Risk groups associated with COVID-19 described: hypertension, diabetes, heart disease, chronic lung disease, chronic kidney disease, immunosuppression, liver pathology, cancer and pregnancy.The participants answered a detailed survey of 24 questions related to COVID-19 disease. Questions were stratified into 4 different sections designed to determine: 1—the degree of exposure to SARS-CoV-2, 2—the diagnosis of the disease, 3—symptomatology and severity of the symptoms and 4—associated risk factors. The responses to each of these sections were analyzed and categorized in different clusters according to the following criteria:62. A significance level of 0.05 was used in bilateral tests. Missing data was multiple imputed using the mice package, based on conditional chained equations, and using the default imputation methods, namely predictive mean matching for numeric variables, logistic regression for binary variables, polytomous regression for categorical data, and proportional odds logistic regression for ordinal variables63. Pooled estimates of parameters and 95% confidence intervals, as well as of p values were obtained afterwards from the multiple imputations64. The rms package was used to derive ordinal logistic models in the proportional-odds version. These models were fitted to predict infection status for the whole dataset, and symptoms severity in the infected stratum of the sample. A wide set of 26 SNPs related to metabolism and nutrition was tested for significance in the prediction of these endpoints, and sex, age, risk, exposition to infection, hypertension, symptoms severity and smoking status were used as adjustment variables. Multiple-test correction of p-values was controlled with the Bonferroni method. The model was validated through bootstrap, using 2000 resamples. An additive model was adopted for the SNPs, where the effect of a homozygotic minor allele genotype is twice the effect of the heterozygotic allele genotype. The use of a codominant or a dominant model did not improve the fit in general, so they were not used. The significance of medication and diet variables was tested by including them in the model in the form of an additive term or an interaction with the rs7412 SNP.The R software, version 3.6.1, was used for all the statistical analysesSupplementary Information.


Aims:Increased left ventricular (LV) wall thickness is frequently encountered in transthoracic echocardiography (TTE). While accurate and early diagnosis is clinically important, given the differences in available therapeutic options and prognosis, an extensive workup is often required to establish the diagnosis. We propose the first echo-based, automated deep learning model with a fusion architecture to facilitate the evaluation and diagnosis of increased left ventricular (LV) wall thickness. Methods and Results: Patients with an established diagnosis of increased LV wall thickness (hypertrophic cardiomyopathy (HCM), cardiac amyloidosis (CA), and hypertensive heart disease (HTN)/others) between 1/2015 and 11/2019 at Mayo Clinic Arizona were identified. The cohort was divided into 80%/10%/10% for training, validation, and testing sets, respectively. Six baseline TTE views were used to optimize a pre-trained InceptionResnetV2 model. Each model output was used to train a meta-learner under a fusion architecture. Model performance was assessed by multiclass area under the receiver operating characteristic curve (AUROC). A total of 586 patients were used for the final analysis . The mean age was 55.0 years, and 57.8% were male. Among the individual view-dependent models, the apical 4-chamber model had the best performance . The final fusion model outperformed all the view-dependent models . Conclusion: The echo-based InceptionResnetV2 fusion model can accurately classify the main etiologies of increased LV wall thickness and can facilitate the process of diagnosis and workup.  Increased left ventricular (LV) wall thickness is frequently encountered in transthoracic echocardiography (TTE) studies, and the common etiologies include hypertrophic cardiomyopathy (HCM), cardiac amyloidosis (CA), and other conditions such as hypertensive heart disease (HTN) ,2. In clWith the recent advance in artificial intelligence (AI) technology, image-based deep learning algorithms have been applied in the field of cardiovascular imaging ,7. SpeciWe hypothesized that a TTE image-based deep learning algorithm with a fusion architecture could accurately classify the important etiologies  of increased LV wall thickness. Our group has proposed a fusion architecture that has the potential to improve the overall model performance ,18 by in99m pyrophosphate scanning or endomyocardial biopsy. Cases were not further divided into the AL- and TTR- subtypes. The HTN/other category was defined as cases that underwent a cardiac magnetic resonance imaging (MRI) for the indication of increased LV wall thickness but were deemed not HCM or CA. The initial review identified 305 HCM patients, 244 CA patients, and 254 HTN/other cases. After patients were identified, six standard TTE views, including apical 2-,3-,4- chamber views , parasternal long-axis view (PLAX), and parasternal short-axis view  and mid-left ventricular (PSAX_V) levels) were collected. The cases were excluded for missingness, incompleteness, or suboptimal image quality in any of the 6 views. Of those patients, 494 qualified  were used for this study. Each study consisted of a combination of the six standard TTE views  with an average of 342 echocardiogram video frames per study. These studies were split into train/validation/test sets with a 72/18/10 split at the study level, with each set containing 358 , 90 , 48  studies, respectively. This retrospective study was approved by the Mayo Clinic Institutional Review Board (IRB). Patients with established diagnoses for increased LV wall thickness (hypertrophic cardiomyopathy (HCM), cardiac amyloidosis (CA), and hypertensive heart disease (HTN)/others) between 1/2015 and 11/2019 at Mayo Clinic Arizona were identified. For HCM patients, the diagnosis was established according to the guidelines, and cardiac magnetic resonance imaging was obtained . For CA As a pre-processing step, echocardiogram videos that are clinically stored in the Dicom format were first processed automatically by extracting frames from the video. Once all the frames of various aspect ratios and image sizes were extracted, the frames were then converted to grayscale images and thresholded at an intensity of 29 to generate contour masks. The intensity threshold was selected empirically by analyzing intensity histogram of the mean image (average image generated from a randomly selected image subset). As seen in To train an end-to-end pipeline, we designed a deep learning-based view classifier model to differentiate between the six standard echo views and an ‘unknown’ class to capture irrelevant/noisy views for this study. The ground truth labels for the images are obtained from the Echo imaging experts. The echocardiogram frames were separated into 256/90/92 at the study level for train/validation/test sets, respectively, so that there was no information leakage across patients. A pre-trained ResNeXt-101 model  was usedWe trained individual parallel models to handle different views see . Multipln = no of frames/video and iP represents the probability calculated for ith class. We trained a logistic regression model as a meta-learner to create a weighted combination of the prediction probabilities from the six view-dependent models’ averaged probability or −1 if the view is missing. We also empirically evaluated the averaging and majority voting aggregation functions for generating fusion, but the weighted combination outperformed the simple aggregation.To further improve the overall performance of the view-dependent classification model, we generated a decision-level fusion scheme (late fusion) where we can leverage predictions from multiple models to make the final decision at the frame level . The decWe computed the GRADCAM (Gradient-weighted Class Activation Mapping) to interpret the performance of the view-dependant models . We direWe performed two distinct ablation studies to understand the impact of certain data components on the trained model in a controlled experimental setting: (1) view level: the importance of each view in the final fusion model, and how the missing views can be handled by the fusion model; (2) chamber level: chamber-related information in the view-dependent AP4 model. For view importance, one view was systematically dropped (at the study level) from the input data and replaced the corresponding model prediction with −1. For chamber-related information, since the AP4 view-dependent model had the best overall performance and is the view that can visualize all four chambers, it was chosen to perform the ablation study. We segmented the heart chamber by using a simple division of the frames in a 60:40 ratio in both the horizontal and vertical axis and obfuscated each quadrant from the AP4 view to generate the partial images. Model performance was assessed as indicated above.We summarized the cohort in The view classifier reached an AUROC >= 0.98 in the classification of all six views . The FleThe view-level ablation study  shows thIn chamber-level ablation, obfuscating quadrant 1 (LV), which represents the left ventricle (LV) of the heart has the most significant drop in the AP4 model performance , which reflects that LV was involved most in all these diseases. Interestingly, removing the portion of any single chamber from the input AP4 image led to a significant drop in performance in identifying CA cases  which reWe successfully established an automatic end-to-end deep learning model framework that accurately differentiates the major etiologies of increased LV wall thickness, including HCM and CA, from the background of HTN/other diagnoses. To the best of our knowledge, this is the first deep learning study that applied multiple standard echocardiographic views with a fusion architecture and achieved an overall superior performance. Additionally, a detailed ablation study highlighting each chamber’s role along with the GradCAM analysis allows for a better interpretation of the model.The major contributions of this work include (1) demonstrating a superior echo-based fusion model performance, especially for CA patients, without any segmentation of the images, (2) providing insights into echo view selection for future study design if not all the views are planned to be used, and (3) showing the possibility of achieving overall superior performance with significantly fewer training cases by a frame-based approach, which will facilitate the development of future models for rare conditions. While the application of deep learning is rapidly growing in medical literature, there are relatively fewer studies that have incorporated a fusion architecture . A fusioOur established automatic deep-learning framework allows the input of the entire echo study. After each view is identified by the view classifier, the probability output generated by each individual view-dependent model is aggregated by the meta-learner to produce the final fusion results. Compared to a video-based model , a frameWith our approach, the human labeling component was minimized to the annotation of echocardiographic views and the target diagnosis. We adopted the current approach specifically to avoid segmentation of the echo images. Human annotation is known to be time-consuming and requires a high level of expertise. However, the consistency of segmentation can still vary between annotators and can hamper the training data quality . AdditioOur work also demonstrated the possibility of reaching a similar performance with significantly fewer training cases compared to the earlier work of Duffy et al. . This apZhang et al.  only use13–15, we observed that the performance of the PLAX model was inferior to the AP3 model (In our study, the performance of the individual view models provided some additional insight into echo-view selection. While the PLAX view was used in all prior studiesP3 model . We beli5. While LV strain has been proposed as a screening tool for CA [Differentiating the etiologies and establishing a diagnosis for increased LV wall thickness remains a challenging task for clinicians ,4,5. CA l for CA , conductl for CA ,29. FurtWe foresee this model being used in daily echocardiography lab practice to improve the initial triage of increased LV wall thickness. This model will be especially useful for labs at institutions with limited diagnostic and or therapeutic resources for the above conditions. Specifically, with the high accuracy in identifying CA cases, this model will largely facilitate the early recognition of these patients and potentially improve the prognosis . The core limitation of this study is that it is a single-center, retrospective study with limited cases. The patients were identified at a tertiary referral center so may not be representative of the general population. Similarly, the quality of echocardiographic images could be different from images obtained in other practices or institutions. While an external validation dataset was sought, the only open-source EchoNet dataset does not contain all the view views for external validation. Given that the existing models only used a single or two views, direct comparison between the studies was not feasible. The workflow of our model did not include the automated process of detecting increased LV wall thickness conditions. However, selecting the cases with known LVH increased the model’s specificity. Compared to a video-based approach, our frame-based approach may have lost certain information about spatio-temporal relationships, but our model had reached an overall superior performance. An online calculator of this model is currently underwork, and we plan to release models and trained weights with the MIT open-source license to benchmark the performance.


Male gender was the only significant factor associated with ThMG. TWAs of the daily MG treatment drug dosages required showed no differences between the groups. Additionally, the rates of exacerbations and crises were not different, but decremental trends were shown in both groups after the thymectomies. (4) Conclusions: The daily dosage requirements of MG treatment drugs were not different. There was a trend of decreasing adverse event rates despite no statistically significant differences during the first 5 years after thymectomy in ThMG and non-ThMG patients.(1) Background: Early thymectomy is suggested in all clinically indicated myasthenia gravis (MG) patients. However, short-term clinical response after thymectomy in MG patients has been limitedly described in the literature. This study aimed to compare the 5-year post-thymectomy outcomes between thymoma (Th) and non-thymoma (non-Th) MG patients. (2) Methods: MG patients aged ≥18 years who underwent transsternal thymectomy and had tissue histopathology reports in Songklanagarind Hospital between 2002 and 2020 were enrolled in a retrospective review. The differences in the baseline demographics and clinical characteristics between ThMG and non-Th MG patients were studied. We compared the time-weighted averages (TWAs) of daily required dosages of pyridostigmine, prednisolone or azathioprine to efficiently maintain daily living activities and earnings between the MG patient groups during 5 consecutive years following thymectomy. Post-thymectomy clinical status, exacerbations or crises were followed. Descriptive statistics were used for analysis with statistical significance set at  Myasthenia gravis (MG) is a common post-synaptic neuromuscular junction (NMJ) disorder in which fatigability or reversible muscular weakness of the eye lid, extraocular, bulbar or limb muscles is the clinical hallmark. MG is an immunologic disorder in which acetylcholine (AChR) or other receptors on the post-synaptic membrane, such as muscle-specific kinase (MuSK), titin, ryanodine receptors, etc. are degraded by immunological mechanisms such as complement-mediated receptor degradation by circulating antibodies, accelerated endocytosis, or functional blockade of the post-synaptic receptors. Diverse clinical presentations have been described, depending on the specific type of receptors affected ,2,3,4,5.The aims of this study were: (a) to compare the baseline clinical characteristics between histopathology-confirmed ThMG and non-ThMG patients, (b) to compare five consecutive years of post-thymectomy outcomes objectively using time-weighted averages (TWAs) of daily dosages of pyridostigmine (a symptomatic drug), prednisolone or azathioprine (immunosuppressants) which were required by the MG patients to effectively maintain their daily living activities and earn their livings (ADLE). The effective outcomes were self-assessed by the patients and discussed between the patients and their physicians before the dosage adjustment. We think this method of co-decision on treatment can accurately represent the individual MG patient requirement of each MG drug for living well. Additionally, (c) we compared the frequencies of exacerbations, crises and deaths due to MG after thymectomy between the two MG patient groups.This retrospective study enrolled MG patients aged 18 years or more who underwent an extensive transsternal thymectomy, and for whom thymic tissue histopathology reports were available from 2002 to 2020 in Songklanagarind Hospital of Prince of Songkla University. The hospital is a 900-bed tertiary-care and referral center serving the lower southern provinces of Thailand. We studied the post-thymectomy outcomes of the MG patients who were followed-up in our service from 1 up to 5 years.We retrospectively collected the patients’ demographic data, pre-thymectomy MGFA classification, time from the diagnosis of MG to thymectomy, thymic tissue histopathology reports, and post-thymectomy daily dosage of the symptomatic drug (pyridostigmine), or immunosuppressant(s) (prednisolone and/or azathioprine) required in the ThMG and non-Th MG patients during the follow-ups at the OPD. We used the TWAs of the MG treatment drugs to report the average daily dosage requirements of the MG drugs to maintain the patients’ ADLEs. We reported the TWAs of the individual drug in six-month intervals, i.e., from 1 January to 30 June and from 1 July to 31 December of each year. The TWA of the daily dosage requirement formula was calculated by the summation of the results from the amount of the individual drug used/day (mg/d) multiplied by the number of days during which the dosage was used, and then, the summation was divided by total days in each six-month interval of a year as follows:(1)“MGFA-PIS” outcome classifications as: complete stable remission (CSR), pharmacologic remission (PR) and minimal manifestations (MM 0–3) following standard definitions.(2)Exacerbation: post-thymectomy MG patients with CSR, PR or MM who had recently developed a clinical progression of MG symptoms significantly greater than that described in each category and had required a symptomatic drug or immune-suppressants (prednisolone or azathioprine) ≥50% of the baseline dosage before the exacerbation.Crisis: the condition of emerging respiratory compromise in a previously stable post-thymectomy clinical status patient, and endotracheal intubation with mechanical ventilation was indicated for respiratory support.Died of MG: an MG patient whose cause of death was directly related to the MG itself or MG treatment complications, or death occurred within 30 days after the thymectomy.“Changes in clinical status”, for which we only studied “exacerbation”, “crisis” and “died of MG”. We did not include “better”, “unchanged” or “worse” because of their subjectivity as mentioned, and they were replaced by the TWAs of MG drug dosages of our study design. We expanded the definitions of exacerbation, crisis and died of MG for this study as follows:The post-thymectomy outcomes in this study were also evaluated by:p < 0.05.The associations between patient demographic data, prethymectomy MGFA classifications, time from diagnosis of MG to thymectomy, prethymectomy requirement of daily dosages of the MG drugs, and the thymic tissue histopathology results reporting thymoma or non-thymoma were analyzed using descriptive statistics. The results are described in frequencies, percentages, means  or medians  as appropriate. The Wilcoxon Rank-Sum test, Fisher exact and t-test were used to assess the significant differences in the variables between the ThMG and non-ThMG patients with statistical significance set at The TWA dosages of the MG drugs required for maintaining ADLEs effectively in each half of the follow-up years are shown in medians (IQRs) and compared between the ThMG and non-ThMG patients. The frequency of cases with different post-thymectomy outcomes using the redefined changes in clinical status of the MGFA-PIS classifications for this study were descriptively compared between the ThMG and non-ThMG patients.Approval to carry out this study was granted following the ethical review by the Ethics Committee of the Faculty of Medicine, Prince of Songkla University . We strictly followed the 1964 Declaration of Helsinki and related amendments as well as good clinical practice guidelines in carrying out clinical research. The analysis was performed in aggregation with all study participants’ personal data fully anonymized to ensure complete protection against disclosing their identities.All data and analysis methods used in this study are published in this article. There are no data deposited in any pre-print depository sources.There were 85 out of 141 post-thymectomy MG patients eligible for data analysis. The rest were excluded due to no thymic tissue histopathological reports being available or no post-thymectomy follow-ups having taken place in our center. Sixty-eight (80%) of the study cases were female. They comprised 65 non-ThMG and 20 ThMG cases according to thymic tissue histopathology reports. Among the ThMG group, the thymic tissue pathology classifications were type AB in 10 (50%), A in 3 (15%) and B in 7 (35%)  cases. From seven cases with data of staging available, there were cases with stage 4 (one), 3A (one) and 1A (five) according to French staging system of thymoma.p = 0.008) but a shorter time interval from the diagnosis of MG to thymectomy  vs. 22.0 , p = 0.03) in the ThMG patients. The blood level of thyroid-stimulating hormone (TSH) was found to be significantly lower in the ThMG patients. More than half of the patients in both MG patient groups were classified as at least grade II B by MGFA clinical classification. There were no differences in baseline MGFA classifications and median daily dosages of individual drugs used for treatment of MG before the thymectomies between the two groups  cases were thymic hyperplasia, while 10 (15.4%) and 2 (3.1%) cases were normal and atrophic thymus, respectively. We found a significantly higher age of onset of MG symptoms  vs. 33 , o groups .p = 0.008) and age of diagnosis ≥42 years , p = 0.005) had significant associations with thymoma by univariable analysis, only male gender was found to have a significant association with thymoma by multivariable analysis , p = 0.046) when adjusted with age of onset and level of TSH.While age at diagnosis of MG , Twenty-three cases were excluded from analysis of TWAs of MG treatment drugs because the follow-up time was less than one year after the thymectomies. Therefore, 62 MG patients (17 ThMG and 45 non-ThMG cases) were followed for MG clinical improvement with variable lengths of time intervals between the consecutive visits, ranging from 1 to 8 months, depending on their MG responsive symptoms. The number of MG patients who continued to have MG treatment drugs after the thymectomies is shown . In compAfter the thymectomies, the patients were followed at the OPD with variable lengths of time intervals, as mentioned earlier. MG-PISs were conducted yearly at the last follow-ups of each year to evaluate the MG status. During the 5-year follow-ups after the thymectomy, most of the patients in both groups were classified as minimal manifestations (MMs) 2–3 according to the MG-PIS, except for a small number of cases in the non-ThMG group, who were assessed as CSR or PR classifications of the MG-PIS, whereas no ThMG patients were assessed as CSR or PR of MG-PIS classifications. We could not assess the statistical differences in post-thymectomy outcomes by MG-PIS between the two patient groups. . The frep = 0.046) when adjusted with the age of MG onset and level of TSH. We think that it is usual for a neoplasm to present at an older age, and early thymectomy is recommended to be performed once a tumor is found from the investigations. A study from Sweden including 326 MG patients who underwent thymectomy and had thymic tissue histopathology reports reported that thymomas were found in 65 cases (19.9%), thymic hyperplasia in 185 cases (56.7%), and normal thymus in 76 (23.3%) cases. Additionally, MG patients who had thymoma in this study had a higher median age (52 years) of onset of MG symptoms than those who had thymic hyperplasia (22 years), or normal thymus (46 years) [Our study found that 20 of 85 (23.5%) of MG patients enrolled in this study were ThMG patients. They had an older age of onset of MG symptoms but a shorter time interval from the diagnosis of MG to thymectomy and a lower blood TSH level compared with non-ThMG patients. There were no differences in the initial MGFA classifications and the dosages of individual MG treatment drugs required before the thymectomies . Only ma6 years) . In gene65 cases .9%, thym6 years) . Therefo65 cases 9.9%, thy6 years) . We thinSince the thymus of an MG patient is the source of post-synaptic receptor autoantibody production, thymectomy is recommended to be performed as early as possible in all generalized MG patients who have no contraindications, especially those who are AChR Ab-positive. This is because thymectomy and long-term and proper-dose immunosuppressive treatment will bring about desirable neurological outcomes ,13,15. RWe found no significant differences in the daily dosage requirements of pyridostigmine, prednisolone or azathioprine as calculated by the TWAs of the individual drugs between the ThMG and non-ThMG patients. Both MG patient groups required comparable dosages of each MG drug to maintain effective ADLEs through the five-year follow-ups . In our In this study, we applied the TWAs of the individual drugs used to control MG symptoms to evaluate the post-thymectomy outcomes instead of the MG-PIS, which was used in most previous studies, because we believed that the TWAs of MG drug dosages required would more accurately reflect the patients’ ability to effectively maintain their ADLEs. As the MG-PIS is roughly categorized into five classes of outcomes based on immunosuppressant and/or symptomatic drugs used and the dosage of symptomatic drugs required in the past year, we thought that this would not provide adequate details of the spectrum of post-thymectomy MG symptoms. Moreover, the one-year time for clinical assessment in the MG-PIS was considered as a crude evaluation and did not represent the actual post-thymectomy clinical status well. Since the clinical conditions of MG fluctuate over time, the use of the TWAs of each MG drug required according to the patients’ self-assessment of their ability to satisfactorily achieve ADLE post-thymectomy in our study was likely to be a more accurate assessment. In our study, the dosages of the individual MG treatment drugs were carefully adjusted after patient-and-physician co-assessments based on the information of daily living and working ability provided by the patients during each follow-up visit. Due to the unequal follow-up intervals ranging from 1 to 8 months of time as mentioned, we thought that the recorded MG-PIS assessments during the patients’ visits to the OPD might inaccurately represent the actual post-thymectomy clinical outcomes objectively and longitudinally. In addition, since most of our MG patients worked in the agriculture or labor sectors, satisfaction with their own ability to maintain their ADLEs after the thymectomies followed by some types of MG drugs would be more suitable for evaluating the post-thymectomy outcomes in our setting. Another study of post-thymectomy outcomes also used the TWAs of quantitative myasthenia gravis scores (QMG scores) and alternate-day prednisolone dosages as outcome evaluators to compare between MG patients treated with thymectomy plus alternate-day prednisolone and with alternate-day prednisolone alone . We consThe post-thymectomy clinical benefits on MG symptoms will not be obvious during the first few years. From our study, it is possible that it would take 5 or more years for significant clinical benefits to manifest. Therefore, all post-thymectomy MG patients still require a range of dosages of MG symptomatic and/or immunosuppression medicines to maintain their ability to effectively carry out their activities of daily living or make their livings while awaiting the maximal clinical benefits to occur. Careful adjustment of the MG medicine dosages in response to each post-thymectomy patient’s requirement for carrying out work and daily activities of living satisfactorily is required. An assessment method such as the TWAs of the MG drugs required by the patients as in this study should be appropriate in most cases for the evaluation of post-thymectomy outcomes, because these reflect the real clinical conditions of the patients in the aspect of satisfactory living and working conditions. We confirm from our findings that post-thymectomy clinical improvement is not immediate after thymectomy. We suggest the use of the TWA of the required dosages of the individual MG treatment drugs as a more objective evaluator for post-thymectomy outcome evaluation. The limitation of this study was its retrospective nature and small sample size. Although the MG-PIS is generally accepted for post-thymectomy clinical evaluation, we suggest that clinical evaluation methods which are able to represent post-thymectomy MG patients’ living conditions well should be developed.


Technologies for micro-to-nanometer patterns of solution-based materials (SBMs) contribute to a wide range of practical applications in the fields of electronics and optoelectronics. Here, state-of-the-art micro-to-nanometer scale patterning technologies of SBMs are disseminated. The utilisation of patterning for a wide-range of SBMs leads to a high level of control over conventional solution-based film fabrication processes that are not easily accessible for the control and fabrication of ordered micro-to-nanometer patterns. In this review, various patterning procedures of SBMs, including modified photolithography, direct-contact patterning, and inkjet printing, are briefly introduced with several strategies for reducing their pattern size to enhance the electronic and optoelectronic properties of SBMs explained. We then conclude with comments on future research directions in the field. Technologies for micro-to-nanometer patterns of solution-based materials (SBMs) contribute to a wide range of practical applications in the fields of electronics and optoelectronics. For example, flexible displays need the integration of circuits with fine pixels onto a flexible substrate. In addition, driving circuits and energy storage devices are required for the operation of flexible information devices. The main challenges to consider for flexible electronics with micro or nanopatterns are low processing temperature and fabrication cost. The patterning processes of solution-based materials (SBMs) are actively researched based on these commercial/industrial demands.5–7 Reducing the overall dimension of flexible electronics is necessary for next-generation information devices including microscale energy storage device, energy generation device, wearable electronics, and portable electronics to be integrated with circuits.2,6,7Recently, interest in flexible, stretchable, and wearable electronics has rapidly increased, especially for the displays of information devices.8 and scanning probe lithography.9 Recently, a sub-10 nm gap structure was reported by using optical lithography with a deep ultraviolet (UV) light source.10 However, the UV light source and/or lift-off process could induce degradation of the active layer and scanning probe lithography with a direct-write and mask-less has limited large-area patterning. On the other hand, patterning processes of SBMs are milder and cheaper than conventional procedures and have a broad applicability, benefitting from easily tailoring chemical and physical properties of solutions and substrates. Because of these various possibilities, many researchers are intensively interested in development and optimisation of patterning techniques for SBMs. Here, we introduce state-of-the-art patterning techniques of SBMs to fabricate micro-to-nanometer scale patterns. This work introduces the printing methods,11,12 solution ordering from surface treatment,13 nano-imprinting,14,15 transfer printing,16,17 and modified photolithography method18,19 to explain the current state of the patterning technology of SBMs. Additionally, various applications, which include various optoelectronics with integrated patterns, are introduced to explain the effects of each patterning procedure.In recent years, the research on micro-to-nanometer scale patterning techniques of SBMs has received increased attention as a strong candidate for the commercialisation in the fields of electronics and optoelectronics. The patterning procedures of SBMs have lower fabrication temperature, fewer process steps, and less waste of materials than conventional patterning procedure including optical lithography, electron-beam lithography,5 Generally, solution ink spreading or film transfers for the desired substrate were used for the patterning of various ink form solutions.11,20 The roll-to-roll (R2R) method has a high speed with broad range resolution, the inkjet printing has middle range speed with medium resolution, and the nano-imprint R2R have low speed with high resolution.5,21 In addition, photolithography technology is used for patterning with few steps such as light exposure with a photomask, deposition, and lift-off without an etching process. The photoresist mixed solution or photoactive molecule attached quantum dot (QD) is directly applied as a photoresist and photoactive layer.18,19 This review introduced a state-of-the-art approaches for micro to nanometer patterning of SBMs that modifies the conventional approach for the solution patterning.We show the schematic for the resolution and printing speed of various patterning technologies .5 Genera2.22Optical lithography  techniques that utilise ultra-violet (UV) light sources, such as KrF (248 nm) laser, ArF (198 nm) laser, or even extreme UV (13.5 nm (EUV) or soft X-rays), have been developed for smaller patterning scale  commonly used in the industry. Thus far, photolithography, which refers to a projection mode, represents the dominant manufacturing approach with physical deposition techniques such as electron-beam  evaporation and sputtering deposition for inorganic electronics and optoelectronics because of its low-cost implementation (mass production), high speed, parallel patterning capability, and high resolution. In academic laboratories, contact photolithography technology commonly utilises a Hg lamp  as a light source to fabricate micrometer-scale patterns of organic and inorganic SBMs because of its low cost, wafer-scale productivity, and accessible applicability to diverse micro-fabrication.23–25 evanescent near-field optical lithography with conformable membrane masks,26 employing surface plasmon polariton with periodic metal masks,27 and beam pen lithography with metal-coated nanoscale apexes on polydimethylsiloxane (PDMS) masks.28–30 In addition, direct writing methods including E-beam lithography (EBL) and scanning probe-based lithography that can provide a high resolution have been suggested to implement fabricating nanopatterns of SBMs into desired substrates. In this chapter we review the materials and processing strategies to form nanopatterned active layer films of inorganic SBMs such as PbS, PbSe, and CdSe cores, and CdSe/CdS core/shell by EBL that appear to have promise for this area.Additionally, in order to define the nanopatterns of resists, modified lithography techniques have been suggested, including near-field photolithography, coupling and guiding light through elastomeric masks,et al.31 demonstrate the nanoscale patterns with PbS, PbSe, and CdSe cores and Zn0.5Cd0.5Se–Zn0.5Cd0.5S core–shell nanocrystals with a variety of ligands.31 The patterns have dimensions as small as 30 nm. The details of the procedures to fabricate nanoscale-patterned nanocrystals are as follows  of octadecyltrichlorosilane (OTS) has been reported without the resist activated by electron beam, which is allowed to create feature sizes as thin as 30 nm with heights of multiple layers and characterise the pattern resolution, robustness, and placement accuracy. Dement bstrates , resultibstrates . A serieobserved .19 This procedure used normal ultraviolet (UV) light sources with pristine ligands without ligand exchanges of QD which were well prevented photoluminescence (PL) degradation of QD material. The oligomer (PO 94F), Irgacure OXe01, and dipropylene glycol diacrylate were used as the photoactive dispersant for CdSe@ZnS QDs. These materials were mixed likely cocktails into propylene glycol monomethyl ether acetate (PGMEA) solvent to create stable colloidal solutions. For the patterning, the conventional photolithography procedures including spin coating, UV exposure, and develop, were exploited as shown in via simple spin casting at the PS with SAM treated substrate. The SAM and patterned PS layer provided directed paths without the bank structure, inducing a surface tension difference. The lower temperature (S-CSC) than the room temperature  was applied onto the substrate to increase the uniformity and result in a more aligned pattern due to reducing the evaporation rate of the solvent during the spin-casting procedure, as shown in via a simple solution-based spin casting procedure.133.The processing technology for making fine patterns must also be developed in accordance with the requirements of the equipment and processes. However, the photolithography technology used in the conventional silicon semiconductor process is limited to the process limit to realise the line width of next-generation devices, and the enormous investment in new equipment must be preceded. Next-generation lithography in this chapter is proposed to fabricate very fine patterns of tens of nanometers.NIT was introduced as new technology to realise a nanoscale line width. Conventional light-based lithography has problems such as mask material, high energy light source and development of photoresist because of the reduction of light wavelength, but the nano-imprint process does not consider the above problems. It is a simple process, and the equipment itself has the advantage of being much cheaper than the EUV or X-ray lithography equipment.37 that was present between the mold protrusion and the substrate to form a nano/micro scale pattern finally. Because heat is applied, the thermal expansions of the stamp and the substrate must be considered, and there is a high risk that the nano-sized protruding portion of the stamp is broken because the relatively high pressure.The nano-imprint process is largely a pattern transfer process through heat treatment and curing by UV irradiation. First, to perform the imprint process, it is necessary to produce a stamp which serves as a mask pattern of the photolithography process. On the mask, the desired pattern is derived from the surface in an embossed pattern. When nano-sized stamps contact a substrate coated with a polymer and heat is applied thereto while applying pressure, the polymer becomes fluid and forms a pattern while filling between the stamp patterns. After cooling, the stamp is removed from the substrate, in order to complete the pattern definition, an additional oxygen plasma dry etching step is used to remove the residual resist layerThis problem can be complemented by a UV-based imprint process, and most of the imprint processes are currently performed on a UV basis. First, when a low viscosity hardening resist is introduced onto the substrate by coating or dipping, contact with the stamp has the advantage that the fluid type resist can be effectively filled between the stamp patterns even at low pressures. A rigid pattern is then formed while the resist is cured by sensitizing the resist through a transparent stamp with a UV light source. This process is performed at room temperature and has a short curing time, which is advantageous for a quick process. Furthermore, this process can perform pattern alignment through the transparent substrate, which is advantageous for the processing of devices with bottom-up structures.38 There have been many technological advances since then. However, most of them are indirect patterning using stamped moulding of nanostructure. Therefore, there is still a limit to the patterning of solution-based organic polymers that are vulnerable to UV or high temperature. However, if the direct nano-imprint of the patterning method is developed in the future, the spread effect is expected to be very large.NIT is used in various applications and is currently undergoing mass production in the memory industry with tens of nanometers. NITs offer various surface nanopatterning possibilities of SBMs and have been developed in the past two decades for various applications including solar cells, light-emitting diodes (LEDs), transistors, and sensors. NITs including micro-contact printing, mould-assisted lithography, hot embossing, and capillary moulding are nonphotolithographic methods that can provide technologically simpler and cheaper nanofabrication strategies, resulting in the potential of high throughput. In 1995, the research team at the University of Minnesota first reported to pattern solution-based organic material directly using nano-imprint lithography technology.3.12, ZnO, PEDOT:PSS, and QDs for electronics and optoelectronics.Hot embossing is essentially the stamping technique of a pattern into organic or inorganic SBM films softened by raising the temperature of the polymer just above its glass-transition temperature or sol solvent evaporation temperature, respectively. The stamp used to define the pattern in the organic or inorganic SBM films can be generally made by replication from Si master mould with the nanopatterns. The benefits of this approach are the ability to take advantage of the wide range of properties of organic or inorganic SBM films, as well as the potential to economically mass produce parts with nanometer-scale features. Here, we review the technologies studied previously, which are the techniques of embossing by using a PDMS stamp or Si master mould to make the nanopatterned inorganic and organic SBM films such as TiO2 with a high surface area has been extensively studied for applications to photocatalysts and photovoltaic devices.39 The convenient embossing procedure of a TiO2 sol film to obtain nanostructures was demonstrated.14 Initially, an ethanol-based TiO2 sol was prepared using tetraorthotitanate, diethanolamine and ethanol under stirring as a precursor.40 To fabricate the pattern of a nanodot, a PDMS mould with nanodot patterns to which a Si original master template was replicated using a nano-moulding process was used as embossing template. As shown in 2 sol solution was spin-coated onto an oxidized Si substrate at 7000 rpm for 30 s. Then, the PDMS mould with the nanodot pattern 42 that enables application to various fields such as thin-film gas sensors,43 photo-detectors,44 and LEDs,45 especially for the UV region. ZnO sol was prepared by dissolving zinc acetate 2-hydrate in DMF with diethanolamine (DEA),46 and the embossing procedure was similar to that of In addition, nanopatterned ZnO and TiN based on embossing technique have been demonstrated. ZnO is an attractive oxide semiconductor with a wide band gap (3.3 eV)47 Among various techniques to fabricate TiN films, a scalable, solvent-assisted soft NIT (embossing) method to quickly generate large areas of nanopatterned crystalline TiO2 or TiN surfaces and structures has been demonstrated.482 nanoparticles in 1,2-propanediol  were spin-coated onto the substrate at 3000 rpm for 15 s. The PDMS mould was placed on the still-wet TiO2 film and then heated at 50 °C for 5 min. Lastly, with removing the PDMS mould, the nanopatterned TiO2 was left on the substrate  of OPV devices needs to be improved, because its PCE is lower than other types of inorganic solar cells. To achieve this goal, one emerging method, NIL, has been suggested which provides an ordered and continuously interdigitated morphology in active layers for both efficient charge separation and collection.51 PEDOT:PSS that is usually used to fabricate solar cells and light-emitting devices as hole transfer layers (HTLs)/electron blocking layers because of their band structure that is compatible with the active layer is spin-coated and embossed by a Si master mould with a 70 nm nanograting pattern at 100 °C and 2 MPa pressure. Then, P3HT:PCBM and LiF and Al were deposited by spin-coating and thermal evaporation, respectively, to fabricate the OPV devices -4H-cyclopenta-dithiophene)-alt-4,7-] (PCPDTBT) was spin-coated and embossed by the Si mater mould at 170 °C and 5 MPa pressure  devices has advanced tremendously, driven by the potential for low cost, large area and flexible devices. devices . Well-de devices  as well  devices . As a repressure . The nanpressure . The cel53,54 Above all, internal and external light extraction methods from the device have highly demanded in QD-LED (QLED) to increase the limited optical out-coupling efficiency of device.55 One of the solutions is the NIL technique. The PEDOT:PSS layer as the HTL was spin-coated on the pre-cleaned ITO glass substrate and embossed using the grating-structured PDMS mould at 80 °C and 10 bar pressure for 300 s. Afterward, PEDOT:PSS with nanogratings was annealed, and other layers for QLED were deposited in order  pixel resolution, which the pixel dimension was 6 μm scale, as shown in 17 In addition, the white QLED with pixilation of the red, green, and blue QD was demonstrated.For the commercialisation of the QD display, the active-matrix QD display was reported 56 Generally, the conventional transfer printing consists of the flat SAM treated silicon substrate used as the donor substrate and the patterned PDMS used for selective detaching of film. In the case of the striping method of patterned QDs (reverse transfer printing), the QDs deposited on a patterned silicon template utilised as a donor substrate, and glass/epoxy backing was used for the selective detaching of the QD layer  technology that can perform three-dimensional patterning with nanoscale structures while solving these problems. They claimed that the method that is applied to a wide range of materials creates a variety of functional structures using a wide variety of inks; unlike other direct patterning methods that use liquid inks such as inkjet printing. They can also be used to make nanometer-sized structures without leaving residues in uncoated substrate areas, and because the filled ink is transferred in the coagulated state before being transferred onto the actual substrate, side-diffusion phenomena do not occur. By using the technology, they demonstrated ZTO nanowire transistors had a field-effect mobility of 0.4 cm2 V−1 s−1, on/off ratio of ∼106 and a threshold voltage of 5 V, as shown in Hwang et al.,105 which is that a solution-based polymer is dried on a flexible/rigid substrate under a suspended flexible PDMS template with groove surface and then a nanoscale wire formation fabricated. This group demonstrates an approach with different drying mechanism to fabricate high-resolution structures via solvent evaporation in confined geometries. A surface-structured flexible template is used to pattern the liquid into capillary bridges and further guide the liquid-drying process with liquid bridge pinning. This technique is combined with an approach with various drying mechanisms for producing nanoscale structures through solvent evaporation in defined spaces. The PDMS template is used to complete the liquid-drying process with pinning while patterning the solution-based polymer into the capillary bridge effect. They demonstrated N/P-type organic semiconductor nanowire transistors had a field-effect mobility of 0.34 cm2 V−1 s−1 , as shown in A pinning of capillary bridge technology was investigated by Li et al.106 reported using a capillary bridge lithography system to align the polymer nanowires including the molecular packing at the desired location. Applying polymer solutions between them using a template having properties of asymmetric hydrophilic top and hydrophobic sidewalls induce constant packing of the polymer chains through solvent evaporation. The average value of the 100 nanowires generated was about 248 nm in width and 150 nm in height. They demonstrated a high sensitivity of 84.7 A W−1 at a wavelength of 532 nm, which is much higher than the spin-coated thin-film photodetector using organic nanowires, as shown in Wei 3.5While chemical synthesis of soluble functional polymers has reached a highly refined level of specialisation, the reality is that patterning on specific substrates and topographies for organic electronics applications still remains a challenge. To acquire fully nanostructured functional polymers, control of patterning processes is required because of the effect of the chemical structure. In addition, traditional processes such as spin casting often do not fully control the formation of the alignment molecular architecture. Functional polymers with particularly large aromatic moieties are of great interest because they induce molecular self-assembly on a substrate surface. Materials with such localised structures are considered important because they can be useful in functional polymer electronics applications. The nanoscale self-assemble pattern method is still limited, but many studies are underway to devise a new method.et al.107 developed a hybrid process that combines conventional photolithography and local surface energy modification through hydrophobic treatment in the vapor phase with tridecafluoro-1,1,2,2-tetrahydrooctyltrichlorosilane using a condensation reaction. Lee et al.108 demonstrated the pattern-formation process that can produce 2D arrays of sub-micrometric size through the principle that is similar to optical interference lithography, which is based on the interference between two beams, split from a coherent laser source, forms a standing wave that is recorded on a photoresist coated wafer to fabricate nanoscale pattern.109,110 However, the solution based pattern-formation process using two waves are formed through the adjustment of the concentration in a dry solution next to the three-phase line or contact line. One wave arises from the solvent evaporation induced solute condensation next to the contact line with the wave vector next to the contact line. Another wave involved here comes from spinodal-precipitation induced by supercooling consisting of wave vectors along the contact line. Li 4.Inkjet printing procedures were well-matured techniques for various patterning and printing applications, which were utilised for the simple printing at paper to micro-circuit fabrication. This method has a simple process with less material waste from direct jetting of the solution for pattern fabrication on the substrate. From these properties, many researchers and companies have focused on the development of inkjet technology.11,20,111–114 Piezoelectric inkjet printer had piezo-device attached nozzle for fine control of the jetting properties. The volume of the ink was well controlled for the 10 pL scale from the piezo jetting process. The microscale patterns were realised from the pico-liter scale droplets. The electrohydrodynamic jet printing device included a microscale print head with a substrate plate and has an electric potential difference between the print head and the substrate, inducing the jetting of the ink. Even though both printing methods have a common point that is a direct solution jetting onto the substrate, a force to jet the ink is different: the inkjet printing used mechanical force for jetting of the ink and the electrohydrodynamic printing used an electrical field for ejecting the solution onto the desired substrate.Inkjet printing methods are composed of the piezoelectric based mechanical jetting and the electrohydrodynamic jetting.Z) of ink.115 Because of the low values of Z, the viscous nature of fluid does not allow drop ejection from the nozzle, whereas a higher value of Z helps in the formation of a large number of satellite droplets. Stable droplet in the case of drop-on-demand (DOD), which related to rheological properties of ink, is determined by the value of Z. Liu et al. has found the limiting value of NWe is 2 < NWe < 25, and the limiting value of Z is 2 < Z < 20 range.116 The lower limit of NWe  could not generate ink-droplets due to lack of capillary force and the higher limit of NWe  leads to the instability of tail in the droplet during drop ejection. Z phase diagram.Physical properties of ink formulation are the most important part of the inkjet research field. The viscosity, surface tension, and density of ink solution have to consider during ink formation. All of these factors are directly connected with Reynolds number (NRe), Weber number (NWe), and Ohnesorge number (Oh), which are factors used to characterize properties of a liquid droplet (115 Copper nanoparticles (∼30 nm) ink allowed conductive copper pattern with 90 μm using inkjet processing, as shown in 113 The dispersion stability of the nanoparticle ink was treated as a key factor with respect to inkjet printing performance. The stabilizer of the smaller metal nanoparticle size was brought to increasing dispersion stability and maintaining a significant amount of copper nanoparticle without aggregation of the metal nanoparticle.115,117With increasing demands for more economic routes to the manufacture of electronic devices, incorporating metal nanoparticle-based printed circuit boards are actively researched. The size of the metal particle in ink has to be considered for stable inkjet processing. Larger particle size and its possibility for aggregation in ink enable to cause clogging of the nozzle. To obtain the high resolution of patterns, the technology to develop ink with smaller metal particle size is required.11 which induced difficulties to implement of nano-sized patterns with inkjet process. For nano-scale patterning via the inkjet printing process, the space-confined assembly method with simple wettability control of the substrate was introduced. First, ink droplets with hydrophilic solvent were printed on a hydrophobic substrate. After printing the droplets, ink droplets were dewetted into dome-shaped dots. The ink solution was dropped onto the patterned substrate and covered with a flat plate, which the step is called a space-confined assembly system. The nanoscale circuits were demonstrated from SEM image of dot patterning with a space-confined assembly. In addition, the line width of the nanoscale circuits was well controlled between 170 nm and 880 nm as changing the concentration of the Ag nanoparticle solution  and composition of the block-copolymers (BCPs) define the size, periodicity and morphology of the patterns.111 Increasing of MWs leads to more amphiphilic character and larger size of building block, which induces larger pattern sizes.118,119 After patterning with hydrodynamic jet printing, thermal annealing procedure is required for removing residual solvent and activation of self-assembly of BCPs. Thermal annealing generates phase separation of the BCPs into domains oriented perpendicular to the surface with periodicities determined by the MWs of the BCPs. In the case of PS-b-PMMA, smaller MWs (25–26k) showed 27 nm of periodical patterns and larger MWs (37–37k) formed 41 nm of patterns size.111 In addition, the pattern of the substrate was well controlled based on the self-assembled nanopatterning processes which were composed of the chemical patterning and physical patterning. These results showed various printed features via hybrids of the electrohydrodynamic jetting with block-copolymer ink.111et al.76 studied an electrohydrodynamic organic nanowire printer which was controlled individually and aligned at a specific substrate position, as shown in x–y stage with a linear motor to place the organic nanowire in the desired position, micrometer to control the tip to collector distance, nozzle of about 100 μm, syringe pump, and high voltage generator. To form the organic nanowire, an electrostatic force is applied to the nozzle with viscous polymer solution, and then the viscous polymer solution is injected into the nozzle by a high voltage applied to the nozzle. This results can be applied to electronics such as transistors and inverter circuits by using N/P-type organic nanoscale wires aligned at a desired position.Min 5.120 DPN processes were actively researched by many researchers as next-generation micro-to-nanoscale patterning processes.121Dip pen nanolithography (DPN) was derived from techniques of scanning probe lithography (SPL). SPL techniques were sorted as physical patterning processes that were constructive or destructive. However, DPN patterning was not a direct contact process between tip and substrate. DPN directly delivers materials to substrate from the tip as a likely fountain pen. Basically, a meniscus formed between the scanning tip and the substrate, which serves as a pathway for ink transport. After Mirkin's report,121 DPN patterning procedures composed of the cantilever and cantilever-free processes. The tip-attached cantilever was a well-known component for DPN patterning procedures. The atomic force microscope (AFM) tip was used to directly pattern of alkanethiols onto a gold substrate, which was the first invention of DPN.120 After this, electrochemical dip-pen nanolithography (E-DPN) procedure suggested for directly patterning of metal and semiconductor materials.122 Tip of E-DPN procedure was used not only ink-transport but also electrochemical reaction to convert precursors to metals or semiconducting materials on a substrate. Thermal DPN (tDPN) was developed, which used a heated tip to melt and deposit of solid-state organic inks on a substrate.123 The tDPN process allowed one to pattern various solid-state materials with an appropriate melting temperature of each material without solvent for dissolving of solid-state materials. In 2006, parallel DPN (p-DPN) processes reported by Salaita et al.124 introduced for large area patterning, benefiting from the 55 000-tip array over one square centimeter.124 The highly-integrated tip array performed a high-throughput DPN process, which was useful to fabricate various sizes, spacing, and shape with high-speed, rather than single tip based DPN. Cantilever-free DPN procedures were developed for large-area patterning in a cost-effective manner. Polymer pen lithography (PPL), which tip made for silicone rubber known as PDMS, was developed from Huo et al.125 PPL array had 11 million pyramid-shaped tips obtained from the simple molding process. PPL process had advantages of DPN with micro-contact printing. However, in a high-resolution, the PPL process had limitations caused by their soft-tips. Hard-tip, soft-printing lithography (HSL) was introduced for the realization of ultra-high-resolution printing with cantilever-free media.126 HSL had ultra-sharp and hard Si tip arrays on an elastomer layer, which elastomer layer acts as deformable spring to support incompressible tips. HSL had 22 nm tip apex, which performed under 50 nm scale pattern size.sn-glycero-3-phosphocholine (DOPC) molecules.127 Patterns of lipid, which is a biomolecule that is soluble in nonpolar solvents, formed with the various scale through transporting lipid ink between cantilever tip and substrate. via simple dwell time control. Short dwell time leads to small size patterns but slightly non-uniform shape and longer dwell time caused a larger pattern size with more uniform shape. 6.In this review, we have systematically introduced various technologies for micro to nanometer patterning of SBMs, and discussed electronic and optoelectronic applications fabricated by various methods of pattering of SBMs. Nanopatterning with modified optical lithography, NIT, transfer printing, capillary bridge pattering with direct patterning, and inkjet printing techniques were introduced to fabricate nanopatterns of SBMs. The tremendous progress for micro to nanometer patterning of SBMs achieved in various new emerging technologies with the evolution of traditional technologies, as shown in this paper. Through these various efforts, nanopatterned SBMs integrated into electronics and optoelectronics have a brighter future.There are no conflicts to declare.


The quality of quantum bits (qubits) in silicon is highly vulnerable to charge noise that is omnipresent in semiconductor devices and is in principle hard to be suppressed. For a realistically sized quantum dot system based on a silicon-germanium heterostructure whose confinement is manipulated with electrical biases imposed on top electrodes, we computationally explore the noise-robustness of 2-qubit entangling operations with a focus on the controlled-X (CNOT) logic that is essential for designs of gate-based universal quantum logic circuits. With device simulations based on the physics of bulk semiconductors augmented with electronic structure calculations, we not only quantify the degradation in fidelity of single-step CNOT operations with respect to the strength of charge noise, but also discuss a strategy of device engineering that can significantly enhance noise-robustness of CNOT operations with almost no sacrifice of speed compared to the single-step case. Details of device designs and controls that this work presents can establish practical guideline for potential efforts to secure silicon-based quantum processors using an electrode-driven quantum dot platform. In particular, a great amount of effort has been put in by researchers to physically realize universal logic gate devices with electron spins in Si-based quantum dot (QD) structures16 whose confinement is controlled with external electric and magnetic fields. The preciseness of corresponding logic operations has been continuously improved so single qubit rotations can be now conducted with a fidelity larger than 99%16, and recently two-qubit entangling operations with a high fidelity are also reported, e.g., 2-qubit SWAP operations with a 98% fidelity8, 2-qubit controlled-Z (CZ) operations with a fidelity larger than 99%14 and 2-qubit synthesized controlled-X (CNOT) operations with a 98.6% fidelity13. Elaborated designs of gate devices that generate quantum entanglement18, the most celebrated quantum resource being widely used in various applications21, have been also reported but their accuracy so far is generally not as good as the non-entangling cases so the fidelity of 2-qubit Bell-states generated from double quantum dot (DQD) platforms stays in 78–97%15. With a rapid progress in pulsing technologies22, the speed of DQD-based gating operations reached a sub-microsecond level, and it is shown that a CNOT operation, one of most crucial entangling logics for universal quantum computing, can be conducted in less than 200 nanoseconds (ns) with a single microwave pulse10.The spin of electrons in isotopically enriched silicon (Si) has been regarded as a promising mechanism for encoding quantum information due to its extremely long coherence time27 that are mainly due to the fluctuation in local electric and magnetic fields around qubits. In the Si-based case, noise of magnetic fields (spin noise) can be suppressed with purification of 29. Suppressing noise of electric fields (charge noise), however, is more difficult than the case of spin noise since its origins have not been fully understood yet. Accordingly, state-of-the-art ideas have been proposed to increase the robustness of spin qubits to existing charge noises in Si devices such as, for example, placing qubits far away from surface oxides27 that can serve as a source of low-frequency charge noises24, increasing spin resonance frequencies7, biasing DQDs symmetrically to reduce the sensitivity of qubit interactions to charge noises30, and decomposing a CZ gate into two CZ/2 gates bridged by an X gate which decouples the quasi-static single-qubit phase noise14. Theoretical concepts have been also suggested for the robustness of entangling gates to charge noise, e.g., using ultra-fast Rydberg interaction for entangling gate in silicon donor31 and optimizing pulse sequences by a neural network to compensate crosstalk of signals under the existence of charge noise32. In spite of the non-trivial contribution driven with these ideas, the up-to-date fidelity of entangling operations in Si devices is not yet in a level where the accuracy in computations can be generally guaranteed, and the motivation for sound studies on technical strategies that can enhance the fidelity of entangling operations under charge noise, therefore, should be huge.In general, the quality of spin qubits in solid-based platforms highly depends on material-inherent noises30. For this purpose, we computationally explore Si DQD structures with our in-house simulation code package that can describe device operations in a full-scale from initializations and time-dependent behaviors of electron spin qubits. As a baseline for discussion, we first model the fast CNOT operation that is driven with a single-step pulse in the recently reported DQD platform10, and quantify fluctuations in fidelity under charge noise by incorporating random noisy potential profiles to device simulations as charge noise can be defined as fluctuations of electric potential energy33. Then, as an alternative way, we implement a CNOT operation with a multi-step control that does not employ AC microwave pulses for generation of entanglement. In spite of the loss in fidelity that happens during the real-time transition of control signals, we find a general pattern that the resulting CNOT operation has remarkably increased robustness to charge noise whilst its operating speed can be maintained in a same order compared to the case of a single-step control. Additional in-depth discussion is presented via rigorous modeling to study the optimal control of multi-step CNOT operations in realistic conditions with a trade-off between the speed and the noise-robustness of operations. Being carried as an extension of our preliminary study that focused on the noise-free addressing of individual qubits34, this work can make a meaningful contribution for Si-based designs of entangling logic blocks that are essential for development of programmable quantum processors.In this work, we elaborately examine the engineering-driven possibilities for devitalizing negative effects that charge noise have against entangling operations implemented with Si QD devices, where the focal point of engineering is the real-time pattern of control signals that has been rarely discussed in detail by the strategies proposed in previous studies10, the target platform is based on a heterostructure that consists of 2 Si and 2 silicon-germanium (SiGe) layers where the fraction of Ge in SiGe layers is 30%. Due to the Si/SiGe band offset, the structure has a natural quantum well along the vertical ([010]) direction and electrons can be confined in the 8 nanometer(nm)-thick Si layer. The lateral ([100]) confinement in the 8nm-thick Si layer is controlled with DC biases imposed on top Ti/Au electrodes  in reality, are also described with Dirichlet boundaries , which has most of electrons and must be solved quantum mechanically, is treated with electronic structure simulations coupled to a parabolic effective mass model36, and the region of SiGe layers (labeled as Bulk Region) is solved with the physics of bulk semi-conductors. For precise modeling of spin states, the electronic structure is calculated with a lateral distribution of the static magnetic field along the [001] direction  can be an initialization point that is beneficial for noise-robust qubit interactions since two QDs can be symmetrically biased30.In any physical platforms, the first step for gating operations is to initialize qubits so the system can be prepared for upcoming control pulses. In the target DQD platform where a qubit state 0 and 1 are encoded to the down-spin (J) between two ground states serves as a source of 2-qubit entanglement in the DQD platform and can be controlled with the middle gate bias that affects the potential barrier between two QDs. In our simulations, J becomes 75.6 KHz at Pinit) and, as shown in Fig. 33. To mimic this 1-step implementation with modeling, we simulate the DQD structure at 33. Simulated 2-qubit responses in Fig. 10.Representing the strength of inter-QD qubit interaction, the exchange energy , the Heisenberg 2-spin Hamiltonian can be completely described with Zeeman-splitting energies of spin states and external magnetic fields, and so are 2-qubit responses of the DQD system. Accordingly, in the regime of a weak interactions that can be represented with the case of J also starts to affect the noise-robustness of gating. As Fig. J is generally much stronger than the J.In the extreme case where the left and right qubit never interact . The Z-rotation  gate has been implemented with a single-step control, but also extend the modeling scope into noise-driven behaviors of the single-step CNOT operation and 1-qubit rotations by incorporating random noisy potential energies into device simulations. Though the 1-step implementation of a CNOT gate in the Si DQD platform has opened the fundamental pathway for securing a fast CNOT gate with simple controls, it severely suffers from charge noise due to unintended fluctuations in the interaction energy between QDs, so its fidelity reaches lower than 35% when the standard deviation of noisy potential energies  system where quantum bits (qubits) are encoded to the confined electron spins. Using a realistic DQD platform based on a silicon/silicon-germanium (Si/SiGe) heterostructure, we make a solid connection to the recent experimental work