Mast et al. analyzed transcriptome data derived from RNA-sequencing (RNA-seq) of COVID-19 patient bronchoalveolar lavage fluid (BALF) samples, as compared to BALF RNA-seq samples from a study investigating microbiome and inflammatory interactions in obese and asthmatic adults . Based on their analysis of these data, Mast et al. concluded that mRNA expression of key regulators of the extrinsic coagulation cascade and fibrinolysis were significantly reduced in COVID-19 patients. Notably, they reported that the expression of the extrinsic coagulation cascade master regulator Tissue Factor (F3) remained unchanged, while there was an 8-fold upregulation of its cognate inhibitor Tissue Factor Pathway Inhibitor (TFPI). From this they conclude that “pulmonary fibrin deposition does not stem from enhanced local [tissue factor] production and that counterintuitively, COVID-19 may dampen [tissue factor]-dependent mechanisms in the lungs”. They also reported decreased Activated Protein C (aPC) mediated anticoagulant activity and major increases in fibrinogen expression and other key regulators of clot formation. Many of these results are contradictory to findings in most of the field, particularly the findings regarding extrinsic coagulation cascade mediated coagulopathies. Here, we present a complete re-analysis of the data sets analyzed by Mast et al. This re-analysis demonstrates that the two data sets utilized were not comparable between one another, and that the COVID-19 sample set was not suitable for the transcriptomic analysis Mast et al. performed. We also identified other significant flaws in the design of their retrospective analysis, such as poor-quality control and filtering standards. Given the issues with the datasets and analysis, their conclusions are not supported. Since the emergence of SARS-CoV-2 in December of 2019, there have been over 230 million reported cases and more than 4.7 million deaths . The sciIn Mast et al. the authors concluded that the extrinsic coagulation cascade regulation in the lung was not majorly impacted by SARS-CoV-2. They proposed that the bradykinin storm mediated pathogenesis originally proposed in The first issue we identified was related to the designation of the BALF bulk RNA-sequencing samples from Michalovich et al (GEO data set - PRJNA434133) as “Healthy Controls” by Mast et al. Analysis of the meta-data associated with the described “Healthy Control” subjects published in Michalovich et al. demonstrates that their samples were overall not healthy and also not representative of the average American population in terms of obesity  (42.4%),The issues with using the samples from Michalovich et al. as the healthy control samples is made clear in the findings of the original manuscript. The study found significant changes in systemic and pulmonary inflammation when comparing individuals with obesity, asthma, or smoking history to their healthy subjects. Specifically, they found elevated levels of circulating inflammatory mediators  and proteins regulating coagulation . Additionally, they reported significant changes in BALF concentrations of C reactive protein, Serum Amyloid Alpha, IL-5, and other proteins that would impact coagulation and inflammation. Gene ontology analysis of transcriptional differences in the BALF that were published in Michalovich et al. identified significant enrichments in tissue remodeling and inflammation ontologies amongst obese and asthmatic groups relative to the three healthy controls. These significant inflammatory, pro-coagulant, and transcriptional changes within the samples that Mast et al. designated as “healthy controls” have many overlapping similarities with the phenotypic changes that are associated with SARS-CoV-2. Such changes would significantly disrupt the ability to accurately characterize SARS-CoV-2 differential expression as these comorbidities are not controlled for in Mast et al. The presence of such disparate sample types within the “healthy control” group does not yield an averaged and more representative control group as was implied in Mast et al., instead the pro-coagulant transcriptional changes associated with the co-morbidities observed in much of the control group would likely mask relevant COVID-19 induced transcriptional changes. Additionally, averaging of highly disparate samples within the control group during differential expression analysis would not yield a more representative data set, but rather would generate a noisy control group with averages significantly weighted towards more abundant sample types.Based on the description of the RNA sequencing library preparation methods described in Zhou et al. and Michalovich et al., very different approaches were used to prepare sequencing libraries. The type of library preparation can significantly modify the RNA content of sequencing libraries via polyA enrichment, rRNA depletion, and other major differences in molecular processes underlying library preparation. Dissimilar libraries, particularly those with non-similar polyA enrichment and ribosomal RNA (rRNA) depletion, cannot reliably be used for differential expression analysis with transcripts per million (TPM) based normalization, which Mast et al. utilized in their analysis .Michalovich et al. uses libraries that are enriched for mRNA via polyA enrichment, while Zhou et al. does not. Michalovich et al. also uses a TruSeq Stranded RNA library Prep kit with RiboZeroTMGold ribodepletion probes. This library preparation approach yields libraries that are selectively depleted of ribosomal reads (which are the predominant RNA species in cells), while enriching for mature mRNA transcripts . By contTo confirm the functional differences in library preparation methods, we analyzed the proportion of reads aligning to rRNA transcripts using the same CLC genomics alignment settings and reference transcriptomes described in Mast et al. This confirmed that the total rRNA content was at a significantly greater proportion in SARS-CoV-2+ patient samples relative to control samples.  The amouRNA-seq approaches for differential expression analysis require that enough sequencing reads be collected to accurately quantify the total expression of transcripts across the genome. In order to have statistical meaningful numbers of reads mapping to each gene for differential expression analysis minimum read depth requirements must be met. If a particular transcript is lowly expressed relative to other transcripts, then a low number of reads may be stochastically detected during sequencing. Such a dynamic could artificially inflate or deflate the relative expression of a particular transcript, especially when normalization approaches are applied to compare libraries sequenced at different depths or with radically different RNA compositions. It is generally accepted in the field that experiments investigating eukaryotic global gene expression typically require at least 30 million poly-A and ribo-depleted reads per sample . In humaIn Mast et al., there are major discrepancies in the relative depths of the sequencing libraries used for the “healthy control” samples and the SARS-CoV-2+ patient samples . Of the To illustrate a specific instance, Mast et al. report that thrombomodulin (THBD) expression in the BALF was decreased by 2200% during SARS-CoV-2 infection. They reported the expression level to be approximately 9.6 counts per million reads in COVID-19 infection and 224 counts per million reads in the control sample set. However, at the level of raw counts, control samples averaged 8,377.68 counts while COVID-19 positive samples averaged 59.88 counts. The normalization process for the counts per million based normalization was further biased by the inclusion of between 16%–80% of the total rRNA in only COVID-19 samples. These rRNA reads would be included in the total number of mapped reads used to calculate the CPM normalization factor in a manner that was not consistent with the normalization of control samples.  Additionally, such a bias would significantly decrease the likelihood of detecting mRNA transcripts in the COVID + genes, including thrombomodulin transcripts. These confounding factors could bring into question the accuracy of the reported magnitude of the differential expression, the reported directionality of the differential expression, and the subsequent pathway analysis performed.The significant issues we have identified regarding the heterogeneity of control samples, dissimilar library preparation methods, and insufficient sequencing depth collectively bring into doubt the validity of many of the conclusions drawn in Mast et al. The normalized manner in which the gene expression data were reported in the supplement and manuscript of Mast et al. made it difficult for reviewers and readers to identify these issues when analyzing the manuscript. Mast et al. additionally did not provide supplemental data regarding the raw reads that were processed during alignment, the raw counts that were normalized and processed during differential expression analysis, or any NGS quality control standards that should have been conducted by the authors before analyzing the data set. From our analysis of their raw data, we conclude that the sample set and experimental design implemented in Mast et al. are fundamentally flawed. The concerns are significantly magnified knowing that others researching COVID-19 are citing these poorly substantiated results in publications  or integUpon processing the raw data as described in our results section, serious issues with relative sequencing depth quickly became apparent. Review of the count data which we have summarized in Table 2 and the differential expression results for genes of interest reported in Table 1 of Mast et al. demonstrate the flawed nature of this analysis. Overall, 23 out of 35 genes of interest reported in Mast et al. average less than 10 mapped reads per gene but were still included in the analysis.  8 of thoBy far the most notable result reported in Mast et al. is the reported observation that tissue factor, the key initiator of the extrinsic coagulation cascade, is not significantly impacted by SARS-CoV-2 infection. They reported no significant difference in expression levels and concluded that tissue factor biology was not a significant factor in the thrombotic complications of SARS-CoV-2 in the lung. They postulated that COVID-19 may dampen tissue factor dependent mechanisms in the lung. This analysis was confounded by the above-described issues including relative depth, rRNA differences between control and COVID sample sets, and normalization This statement is important as the field has also begun converging on tissue factor as a key player in the pathogenesis and coagulopathy complications of SARS-CoV-2 infection. For instance, patients with COVID-19 have been shown to have elevated levels of tissue factor laden microvesicles circulating in their blood, along with other markers of the extrinsic coagulation cascade . FurtherAt the time the manuscript was submitted, several higher quality data sets were available and the authors of Mast et al. should have redone their analysis on sample sets that were collected with the intent of resolving transcriptomic signatures to accurately characterize the host response to SARS-CoV-2 . Additio


In the search for effective therapeutic strategies for depression, repetitive transcranial magnetic stimulation (rTMS) emerged as a non-invasive, promising treatment. This is because the antidepressant effect of rTMS might be related to neuronal plasticity mechanisms possibly reverting connectivity alterations often observed in depression. Therefore, in this review, we aimed at providing an overview of the findings reported by studies investigating functional and structural connectivity changes after rTMS in depression.A bibliographic search was conducted on PubMed, including studies that used unilateral, excitatory (⩾10 Hz) rTMS treatment targeted on the left dorsolateral prefrontal cortex (DLPFC) in unipolar depressed patients.The majority of the results showed significant TMS-induced changes in functional connectivity (FC) between areas important for emotion regulation, including the DLPFC and the subgenual anterior cingulate cortex, and among regions that are part of the major resting-state networks, such as the Default Mode Network, the Salience Networks and the Central Executive Network. Finally, in diffusion tensor imaging studies, it has been reported that rTMS appeared to increase fractional anisotropy in the frontal lobe.The small sample size, the heterogeneity of the rTMS stimulation parameters, the concomitant use of psychotropic drugs might have limited the generalisability of the results.Overall, rTMS treatment induces structural and FC changes in brain regions and networks implicated in the pathogenesis of unipolar depression. However, whether these changes underlie the antidepressant effect of rTMS still needs to be clarified. No limitation was posed regarding publication date. We included studies using unilateral, excitatory, high-frequency (⩾10 Hz) TMS treatment targeting the left DLPFC. Only studies that investigated brain structural and FC using whole-brain neuroimaging techniques before and after rTMS protocols in depressed patients were included. Studies (a) employing other techniques , (b) based on bilateral or inhibitory rTMS protocols, or (c) targeting areas other than left DLPFC were excluded. The reference list of the selected articles was checked in order to find relevant references not emerged from the main query. Only 13 studies were selected as eligible. Of these, two studies included, in addition to unipolar depressed patients, a small cohort of depressed bipolar disorder type II patients. Finally, nine studies used resting-state functional magnetic resonance imaging (rs-fMRI), three studies employed diffusion tensor imaging (DTI) techniques, and one study employed single-photon emission computed tomography (SPECT).Connectivity changes induced by rTMS treatment are briefly discussed below, divided according to the investigated connectivity domain. FC results focused on two brain areas, the DLPFC and the subgenual anterior cingulate cortex (sgACC), whose connectivity emerged to be affected by the selected rTMS protocol. Although our focus was on connectivity changes from before to after rTMS, we also listed, when reported, the baseline features predictive of treatment response.et al. , a decrease in FC between sgACC and DMN, consistently with the result reported by Liston et al. (v. sham) on the Montgomery-Åsberg Depression Rating Scale (MADRS) and FC was demonstrated, suggesting that reduction in FC between sgACC and DMN may parallel the reduction in depressive symptoms, with no specific effect of active v. sham rTMS. Moreover, with regards to the CEN, the authors found a decrease in FC between sgACC and CEN. This last result is in contrast with the one reported by Liston et al. , a marker of white matter microstructure, measured through DTI  and major resting-state networks ) were found to be associated with rTMS treatment, possibly mediating rTMS therapeutic efficacy.et al., et al., et al., et al., et al., et al., et al., In particular, in the reviewed studies, a decrease in FC between DLPFC  is part of the SN, a key circuit directing attention and cognitive control Menon, , and comet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The three DTI studies here reviewed (Kozel et al., et al., The reviewed studies suffer from some limitations. First, the sample size was often modest and some studies (Liston In conclusion, the abovementioned results support the hypothesis that rTMS induces neuronal plasticity and reorganisation of key networks in the pathogenesis of unipolar depression. However, whether these changes underlie the antidepressant effect of rTMS is not defined yet. Further studies including larger and more homogeneous samples are needed to better clarify the effect of rTMS on brain connectivity and the relationship with its therapeutic effect in unipolar depression.All data described in this review have been included in


Dear Editor,The diverse microbial community present in the human intestine plays a vital role in translating the food to nutrients and metabolites essential for maintaining host physiology, including digestion, lipid and glucose metabolism, immune homeostasis, and proper development of the brain and cognitive functions . Consumal., 2018). Modulaal., 2018). The poal., 2018; Ángel Gal., 2018). A deepal., 2018; Conternal., 2018; de Olival., 2018; Guevaraal., 2018; Istas eal., 2018; Lima etal., 2018; Medina-al., 2018; Ntemirial., 2018; Park etal., 2018; Vilela al., 2018) summariThe authors thank the American University of Ras Al Khaimah for the support and facilities provided.The authors declare no conflict of interest.


Khatouri et al., RSC Adv., 2021, 11, 7059–7069, DOI: 10.1039/D0RA09804C.Correction for ‘Effect of hydrophobically modified PEO polymers (PEO-dodecyl) on oil/water microemulsion properties:  The authors regret that the name of one of the authors  was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


Dear editor,We are grateful for the comments of “Earliest details of Dermatology by Ayurveda”Similarly, we are grateful for the comments by Mirzaei MR et al.None declared.Iago Gonçalves Ferreira: Conception and/or design of the study; literature review and article selection; content analysis; results analysis; preliminary review and final drafting.Magda Blessmann Weber: Conception and/or design of the study; literature review and article selection; content analysis; preliminary review and final drafting.Renan Rangel Bonamigo: Conception and/or design of the study; literature review and article selection; content analysis; preliminary review and final drafting.None declared.


Childhood trauma is associated with an elevated risk for psychosis, but the psychological mechanisms involved remain largely unclear. This study aimed to investigate emotional and psychotic stress reactivity in daily life as a putative mechanism linking childhood trauma and clinical outcomes in individuals at ultra-high-risk (UHR) for psychosis.N = 79 UHR individuals in the EU-GEI High Risk Study. The Childhood Trauma Questionnaire was used to assess self-reported childhood trauma. Clinical outcomes were assessed at baseline, 1- and 2-year follow-up.Experience sampling methodology was used to measure momentary stress, affect and psychotic experiences in the daily life of β = −0.14, p = 0.010) and negative affect  was modified by transition status such that stress reactivity was greater in individuals who transitioned to psychosis. Moreover, the association of stress with negative affect  and psychotic experiences  was greater in individuals exposed to high v. low levels of childhood trauma. We also found evidence that decreased positive affect in response to stress was associated with reduced functioning at 1-year follow-up . In addition, there was evidence that the association of childhood trauma with poor functional outcomes was mediated by stress reactivity , but no evidence that stress reactivity mediated the association between childhood trauma and transition .The association of stress with positive (Emotional and psychotic stress reactivity may be potential mechanisms linking childhood trauma with clinical outcomes in UHR individuals. The effects of childhood trauma will be mediated via pathways through stress reactivity (i.e. a mediation model).Furthermore, other possibilities of how childhood trauma and stress reactivity may combine with each other may be relevant  the magnitude of associations between momentary stress and negative affect, positive affect and psychotic experiences is modified by transition status, and (ii) the effect of childhood trauma on transition status will be mediated via pathways through stress reactivity (i.e. a mediation model).et al., et al., The sample comprises UHR individuals from London (UK), Melbourne  and Amsterdam/The Hague (the Netherlands) recruited as part of the EU-GEI High Risk Study . The target constructs  show high and continuous variation over time. To obtain a representative sample of participants’ experiences in daily life and to capture relevant variation in these target constructs with high resolution, a time-contingent sampling design with a blocked random schedule and a high-sampling frequency was used for ESM data collection, i.e. ten times a day for six consecutive days at random moments within set blocks of time , an established 25-item self-report measure enquiring about traumatic experiences during childhood . Second, we added two-way interaction terms for stress × childhood trauma to examine whether the associations between momentary stress, negative affect, positive affect and psychotic experiences were modified by childhood trauma (H2). The hypothesis that the associations of momentary stress with affect and psychotic experiences were greater in individuals exposed to high v. low levels of childhood trauma  was tested by using the ‘testparm’ command for computing Wald tests to assess statistical significance of two-way interaction terms and the ‘lincom’ command to compute linear combinations of coefficients  nested within participants (level-2), the ‘mixed’ command in Stata 15 was used to fit two-level, linear mixed models . To control for confounding of findings by comorbid disorders, all analyses were controlled for comorbid major depressive and anxiety disorders. In addition, analyses for testing H3 and H4 were controlled for time to follow-up to account for variation in time to follow-up. Unadjusted analyses and sensitivity analyses in a restricted sample assessed in a ±6 month time interval around the expected follow-up time points are displayed in online Supplementary materials 4–6.Restricted maximum-likelihood (H1 and H2) or maximum-likelihood estimation (H3 and H4) were applied, allowing for the use of all available data under the relatively unrestrictive assumption that data are missing at random and if all variables associated with missing values are included in the model . Assessment of clinical outcomes was completed for 48 participants at 1-year follow-up  and 36 participants at 2-year follow-up . Nine individuals (11%) transitioned to psychosis by the final follow-up time point. Participants were on average 23 years old (s.d. = 4.93) and 56% were women. The majority (67%) of the sample was white, followed by 15% with black ethnicity. Seventy-six percent of the participants were diagnosed with a comorbid axis I disorder. Comparing the current study's participants to individuals included in the EU GEI High-Risk study, for whom ESM data were not collected (N = 266), there were no differences in demographics  or overall prevalence of comorbid disorders . However, the current sample showed higher levels of childhood trauma , a higher prevalence of specific phobias  and a lower prevalence of major depressive disorder  compared to participants, for whom ESM data were not collected  0.27 to 0.36, p < 0.001) and psychotic experiences  as well as with a moderate decrease in positive affect .Momentary stress was associated with small to moderate increases in negative affect  and psychotic experiences . Furthermore, we found a non-significant indication that childhood trauma modified the association between momentary stress and positive affect .Childhood trauma modified the associations of momentary stress with negative affect  and lower level of functioning  at 1-year follow-up .B = 1.74, 95% CI 0.36 to 3.11, p = 0.016). Moreover, perceptual abnormalities at 1-year follow-up were predicted by emotional  and psychotic stress reactivity . There was no evidence that emotional or psychotic stress reactivity predicted anxiety or tolerance to normal stress.Decreased positive affect in response to stress was associated with higher illness severity . We found no evidence that emotional and psychotic stress reactivity mediated the association of childhood trauma and level of functioning. The association of childhood trauma and unusual thought content at 2-year follow-up was mediated by increased negative affect in response to stress . In addition, the association of childhood trauma and perceptual abnormalities at 1-year follow-up was mediated by increased negative affect  and psychotic experiences in response to stress . High levels of childhood trauma were associated with more intense reactivity in the form of a stronger increase of negative affect and psychotic experiences in response to stress, which, in turn, was associated with higher illness severity, unusual thought content and perceptual abnormalities at follow-up. We found no evidence for direct effects of childhood trauma on anxiety and tolerance to normal stress and no mediation via stress reactivity.In exploratory analyses, there was no evidence for a direct effect of childhood trauma on transition status and no mediation via stress reactivity .Using an experience sampling design, we found strong evidence that minor daily stressors were associated with emotional and psychotic stress reactivity in UHR individuals (H1). Childhood trauma modified the effect of daily stressors on negative affect and psychotic experiences, with more intense psychotic experiences and stronger increases in negative affect for individuals exposed to high levels of childhood trauma (H2). In addition, we found some evidence to suggest stress reactivity predicts clinical outcomes at follow-up (H3). Finally, there was partial evidence that stress reactivity mediates the association of childhood trauma and clinical outcomes (H4).et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The reported findings should be interpreted in light of several methodological considerations. First, childhood trauma was measured with a retrospective self-report questionnaire. A common concern about retrospective self-report is that recall bias and cognitive distortions might lead to invalid ratings (Dill et al., et al., In accordance with previous ESM studies, we found that momentary stress was associated with small to moderate increases in negative affect and psychotic experiences and moderate decreases in positive affect in UHR individuals (Reininghaus et al., et al. (et al., et al., et al., et al., et al., et al., et al., et al., When considering the role of childhood trauma and stress reactivity in clinical trajectories, several possibilities of how these may combine with each other may be relevant (Schwartz and Susser, , et al. , we inveet al., et al., et al., et al., Taken together, our findings underscore the relevance of reactivity to daily stressors as a putative mechanism linking childhood trauma with clinical outcomes in UHR individuals. Adding evidence to the mediated synergy model, the study suggests early adversity in childhood links to more severe clinical trajectories via, and in interaction with, subsequently elevated stress reactivity in adulthood. Therefore, the findings underline the relevance of ecological momentary interventions targeting stress reactivity in daily life (e.g. EMIcompass, a transdiagnostic ecological momentary intervention for improving resilience in youth; Schick


Prostate cancer (PCa) is one of the most frequently diagnosed malignancies of men in the world. Due to a variety of treatment options in different risk groups, proper diagnostic and risk stratification is pivotal in treatment of PCa. The development of precise medical imaging procedures simultaneously to improvements in big data analysis has led to the establishment of radiomics - a computer-based method of extracting and analyzing image features quantitatively. This approach bears the potential to assess and improve PCa detection, tissue characterization and clinical outcome prediction. This article gives an overview on the current aspects of methodology and systematically reviews available literature on radiomics in PCa patients, showing its potential for personalized therapy approaches. The qualitative synthesis includes all imaging modalities and focuses on validated studies, putting forward future directions. In global cancer statistics of men prostate cancer (PCa) is the most frequently diagnosed malignancies in the world and the fifth leading cause of death worldwide The Radiomics Pipeline Figure  is the e(1) Image acquisition and preprocessing(2) High-throughput feature extraction(3) Data integration and data analysisThe Image Biomarker Standardization Initiative (IBSI) published a reference manual to harmonize the feature extraction by providing (i) definitions, (ii) a standardization of the radiomics pipeline, (iii) reference datasets and (iv) a reporting scheme e.g., by intensity inhomogeneity correction or noise filtering for MR-images All imaging modalities mentioned in the introduction can be utilized for PCa radiomics: TRUS, MRI, PSMA-PET, CT and bone scan. It is important to mention that heterogeneities in image acquisition und image reconstruction algorithms due to different local standards are culpable for missing repeatability and reproducibility of RF The spatial and gray level information of the segmented voxels is used in numerous mathematical calculations to extract pre-defined “hand-crafted” RF. They can be computed with various open-source packages like PyRadiomics e.g., the depth of a tree or a deep-learning architecture and (iii) one test set for the final assessment. The latter might be used independently for validation. During cross-validation (CV) usually small datasets are divided accordingly in an iterative process. K-fold CV partitions the dataset in k subsets using one as a validation and the rest for training. This process is repeated for each subset. Leave-one-out CV operates similarly but leaves one patient for validation while using the rest for training CV should be used with caution especially with leave-one-out CV tending to be overly optimistic Often a vast number of RF are computed, and the abundance of RF demands feature selection and/or reduction to avoid overfitting and to exclude not relevant or redundant features. Many features are correlated with each other; these redundant features might be depicted with heatmaps and should be omitted st order features and texture features. Shape features describe the morphology of the VOI for instance the size, volume or diameter. 1st Order features are based on an intensity histogram derived of the segmented voxels et al. the gray level co-occurrence matrix (GLCM) assesses the gray levels of pairs of neighboring voxels “Hand-crafted” RF st of January 2014 st of January 2021. 251 articles were located. Additionally, 22 manuscripts were identified through other sources . 35 duplicates were removed. Only articles that met inclusion criteria were included. Finally, 77 studies were included in the qualitative synthesis. Please see Figure Studies eligible for inclusion complied with the following criteria: articles had to be on PCa radiomics with predefined “hand-crafted” features derived from MRI, TRUS, CT, Choline- or PSMA-PET and needed to apply internal or external validation. Excluded were papers not written in English and non-original articles. Two of the co-authors (SKBS and ASB) performed independently a PubMed/Medline, EMBASE and Cochrane Library database search for the terms: (cancer of prostate[MeSH Terms]) AND ((texture features) OR (radiomics)). If the two independent readers included or excluded studies differently a third reader (CZ) decided on eligibility. This was performed in 11 cases. The time period considered in this literature review was from 1Furthermore, ongoing clinical trials were screened on “clinicaltrials.gov”. Studies eligible for inclusion fulfilled the following criteria: ongoing trials on PCa RFs with “hand-crafted” features derived of MRI, TRUS, CT or PSMA-PET. Trials with unknown status were excluded. CZ performed the search for the terms (“Condition or disease: prostate cancer” AND “radiomicsl” OR “texture features”). Six trials were located, and one trial (NCT03294122) was excluded due to unknown trial status.Literature research revealed 57 original papers computing RF on multiparametric magnetic resonance tomography (mpMRI) imaging  et al. proposed a RF based framework for PCa detection and localization et al. (ROC-AUC 0.683-0.768 across 3 sites), showed good area under the receiver operating characteristics curve (ROC-AUC) for PCa detection et al. developed a framework of combined T2w, DWI and DTI features for differentiation of PCa and non-PCa voxels et al. demonstrated that the addition of DCE-RFs does not improve performance of T2w and DWI-RF based models to detect clinically significant PCa in the PZ et al. showed lower results for a PZ specific classifier for PCa detection with ROC-AUC of 0.6-0.71 In two preliminary studies, Cameron et al. introduced novel RF based on Joint Intensity Matrix to predict GS (ROC-AUC 0.64-0.82 depending on GS groups) et al. however, could not show that ADC features were predictive for GS upgrading in intermediate-risk prostate cancer et al. demonstrated that RF and quantitative histomorphometry correlate and are predictive for GS et al. investigated the prediction of clinically significant PCa (GS≥7) in PIRADS 3 lesions, which could be a useful tool for biopsy guidance et al. reported that RFs from T2w and DWI sequences are associated with clinically significant PCa, being even more relevant than PIRADSv2 evaluation in some patients GS prediction and discrimination were assessed in 22 studies et al. and Zhang et al. showed that mpMRI derived RFs show good performance for bone metastasis prediction in untreated PCa with an ROC-AUC up to 0.92 et al. externally validated an ADC based RF (SZEGLSZM), which was identified in a previous study et al. demonstrated a ML classifier derived from T2w and ADC RF with good prediction of BCR after surgery or RT. which was externally validated with a AUC of 0.73 et al. showed good performance for BCR prediction after RT of localized PCa et al. elaborated a quality system to asses automated prostate segmentations with external validation et al. and Giannini et al. addressed RF-based PCa segmentation Five studies investigated RF for the prediction of extracapsular extension and reported high AUC values between 0.80-0.90 for radiomic signatures based on T2w and ADC sequences Literature research revealed five original papers et al. reported two distinct RFs  with good performance to detect significant PCa lesions not visible in PSMA-PET/CT. This result was externally validated by an independent cohort et al. demonstrated a RF based machine learning model to predict lymph node involvement, presence of metastases, GS prediction (≥8) and presence of extracapsular extension Three studies aimed for GS discrimination Literature research revealed six original papers using CT scans et al. implemented RF for automatic prostate gland delineation in TRUS images et al. suggested that RF derived from CT images might enhance interpretation of treatment response of bone metastases et al. demonstrated that RFs derived from CT images of PSMA-PET/CT scans could accurately distinguish between metastatic lesions and sclerotic area et al. outperformed conventional measures for detection of lymph nodes metastases GS discrimination by RF was the aim of four studies using TRUS In total, 5 studies were identified using mpMR imaging n = 4), PET (n = 1), CT (n = 1) and bone scans (n = 1) to extract RF  may outperform biopsy mapping for GS 7 vs ≥8 discrimination et al. examined the PSMA expression in a combined cohort of more than 18 000 radical prostatectomy specimens and observed a correlation between PSMA expression and the GS The other focus is GS discrimination, reflecting the need for improvements in risk stratification. It is not surprising that most of the studies chose GS discrimination, since GS is the most established histologic biomarker. In clinical routine, the GS before primary PCa therapy is evaluated in tissue cores obtained by biopsy. However, due to intratumoral heterogeneity the GS in biopsy cores and prostatectomy specimen is discordant in 20-60% of the patients e.g. by genomic analyses) might outperform GS for risk prediction et al. showed weak correlations between RF and hypoxia gene expressions, providing an opportunity to assess the hypoxia status in PCa et al. and Switlyk et al. demonstrated an association between RF and the genetic marker phosphatase and tensin homolog et al. identified radiomic signatures which reflected genes that are over- and underexpressed in aggressive prostate cancer et al. suggests that RF signatures could distinguish between lesions of different aggressiveness However, several studies proposed that a thorough analysis of PCa tissue characteristics  address extraprostatic extension (n = 6), BCR (n = 6), segmentation (n = 4), bone metastasis (n = 3), lymph node detection (n = 3) and radiotherapy toxicity (n = 2). Considering that most PCa patients are long-term survivors after treatment a reliable prediction of toxicity is warranted. Due to the lack of predictive models for toxicity prediction, we consider this field of major interest for future studies. Some of the excluded studies featured interesting concepts for the use of radiomics and treatment associated toxicity in PCa patients. Radiotherapy toxicity prediction was investigated for femoral head fractures Overall, most of the included studies presented good to high AUC values. However, these findings need to be considered diligently regarding publication bias and the variability observed in RF. As illustrated above the radiomic pipeline is a sequence of operations and each operation can be modified et al. developed a 3D printable phantom to measure repeatability and reproducibility of MRI-based radiomic features which could facilitate multi-center studies to harmonize image protocols and thereby tackling some of these challenges Texture features are increasingly sensitive to acquisition parameters with growing spatial resolution Multiple segmentations can reduce variability and bias in RF extraction of manually, semiautomatically or automatically segmented VOIs et al. investigated different generally adopted image intensity normalization techniques for T2w-MRI images and demonstrated a relevant impact on reproducibility of RFs Isaakson et al investigated normalization techniques to enhance comparability across different subjects and visits et al. investigated the variability of RF in MRI by using different filters, normalization, and image discretization techniques and observed that RF were sensitive to these pre-processing procedures. Hence, they recommended detailed reporting of the pre-processing steps and the use of open-source software et al. reported that ComBat harmonization is efficient and enables MRI data pooling from different scanners and centers Schwier et al. investigated repeatability of RF derived from CBCTs and reported that only five radiomic features were repeatable in < 97% of the reconstruction and preprocessing methods et al. proposed an approach to assess RF stability without multiple acquisitions and segmentations that could be used for preliminary RF selection. In addition, the authors advocated that RF derived of ADC maps behave differently based on the region extracted e.g. RF derived from head and neck tumors are less stable than those derived of sarcomas et al. recommends to investigate the repeatability of RF for every tumor type as well and for every PET-Tracer Two studies investigated repeatability of MRI-derived RFs and concluded that repeatability of many RFs is moderate and that a set of reproducible image features is desirable These papers demonstrate the fragility of RFs and the need of reproducible RF sets in order to enable a broad clinical application.et al. pitfalls could be uncovered and described Consequentially, more research on prostate MRI and PSMA-PET RF robustness should be performed. Other approaches to tackle RF variability is the standardization of RF definitions and calculations which IBSI tries to promote Nevertheless, validation is pivotal considering the variability of RF. 35 of 238 articles were excluded due to missing validation. In internal validation different types might be utilized like the aforementioned ML algorithms, k-fold CV or leave-one-out CV, as well as independent datasets for model development and validation. A proper methodology and the separation of training and validation dataset is demanded at all times et al. used deep learning in combination with “hand-crafted” features and has successfully applied it in differentiating unilateral breast cancer from low-risk patients Many studies used ML for model building and verification. ML and deep learning as a subfield are emerging and harbor great potential This review focusses on the clinical aspects of RF demonstrating its great potential to affect management of PCa. However, some technical aspects have not been further investigated: information on the used algorithms for RF extraction or ML approaches were not provided. Additionally, we did not state whether the published models or the parameters are publicly available.In conclusion, most research in PCa radiomics focuses on PCa detection and GS discrimination. MRI as SoC is the most used imaging modality for RF computation for now, but PSMA-PET is gaining evidence in a wide variety of clinical settings. Most of the results suggest good to high performance of radiomics models but should be considered carefully due to RF variability. Further research is demanded on RF sensitivity and robustness especially on RF extracted of prostate MRI and PSMA-PET.


Inflammation is divided into acute inflammation and chronic inflammation. Chronic inflammation has been proved to be one of the major culprits of tumor occurrence and development . Once acLiu et al. described the role of IL-17A in Chronic Obstructive Pulmonary Disease (COPD), and discussed that IL-17A and its downstream regulators are potential therapeutic targets for COPD and subsequently COPD-derived lung cancer. Zhang et al. explored the role of FDX1 in the prognosis and metabolism of lung adenocarcinoma. They showed that FDX1 was closely related to glucose metabolism, fatty acid oxidation and amino acid metabolism. Another interesting study performed by Zeng et al. found chemokine ligand 14 (CXCL14) is involved in the proliferation and migration of ROS-induced colorectal cancer (CRC) cells, suggesting that aberrant ROS may promote colorectal cancer cell proliferation and migration through an oncogenic CXCL14 signaling pathway. Also, Wang et al., from another aspect, discussed the carnitine palmitoyltransferase system as a new target for anti-inflammatory and anti-cancer therapy, which may work as a promising anti-inflammatory/anti-tumor therapeutic strategy for numerous disorders. In tumor microenvironment field, Du et al. studied the tumor microenvironmental m6A as a prognostic biomarker associated with the hepatocellular carcinoma (HCC). And Wei et al. found that inhibition of BCL9 modulates the cellular landscape of tumor-associated macrophages in colorectal cancer.Here, we are committed to developing new strategies and treatments to activate the immune system of patients with chronic inflammation and cancer, in order to discover new drugs that can be used to combat chronic inflammation and induce cancer immune activation. In our research topic, Wu et al. explored T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), which is highly expressed in a subset of Treg cells, as a novel target for bladder cancer immunotherapy. Li et al. discussed the cGAS-STING pathway to explore the DNA immune recognition regulation in autoimmune disease and cancer. They summarized the current progress on cGAS-STING pathway modulators and laid the foundation for further investigating therapeutic development in autoimmune diseases and tumors. Wang et al. discussed the inhibitory effect of methylseleninic acid on esophageal squamous cell carcinoma through EGFR-IL-6 signaling axis. For metastatic cancer, Guo et al. used a xenograft model in zebra fish, and found lncRNA OR3A4 acts as the inflammatory cytokine to promote the proliferation and metastasis of ovarian cancer through KLF6 pathway.Today, in cancer prevention and treatment, many clinical trials aiming at evaluating the efficacy of inflammatory regulators are underway. Though the single use of anti-inflammatory drugs has shown limited efficacy in cancer treatment, inflammation modulators can synergistically increase the anti-cancer drug’s efficacy in cancer therapies . For example, in some patients with advanced cancer, after conventional treatment, immunotherapy can still alleviate or even prevent the further development of disease . It is wIn summary, the collection of aforementioned articles in this research topic provide either overview of novel targets in immunotherapy, or new fundamental findings and summaries related to chronic inflammation and cancer. Additional researches, for example, drug delivery systems and synthetic antibody engineering, are needed to gain further insights as we move toward to improve the safety and efficacy of novel immunotherapy applications in chronic inflammation and cancer.


Stroke is a multifactorial disease and an extremely serious and socially important medical condition ,2. A recThis Special Issue (SI) entitled “Genomics of Stroke” provides a platform for a wide range of papers related to genetic studies of the pathogenesis, progression, diagnosis, and treatment of stroke. This SI includes six research articles and four reviews.The research articles in our SI are focused on association and functional studies of stroke-related genes or noncoding RNAs, and model systems, as well as pharmacogenomics and bioinformatics studies of stroke.First, we consider a paper entitled “MicroRNA Analysis of Human Stroke Brain Tissue Resected during Decompressive Craniectomy/Stroke-Ectomy Surgery” by Carlson et al. It should be noted that the authors conducted a comprehensive study. Specifically, human brain samples were obtained during craniectomy and brain tissue resection in patients with severe stroke who had life-threatening brain swelling. The tissue samples were subjected to histopathological and immunofluorescence microscopy evaluation, next-generation miRNA sequencing (NGS), and bioinformatic analysis . As a reThe role of another type of regulatory RNA—namely, circular RNAs (circRNAs), in cerebral ischemia conditions was studied by Filippenkov et al., as reported in their paper entitled “Genome-Wide RNA-Sequencing Reveals Massive Circular RNA Expression Changes of the Neurotransmission Genes in the Rat Brain after Ischemia–Reperfusion”. This type of RNA remains a highly promising target for research. Filippenkov et al. conducted a genome-wide RNA-Seq analysis of the subcortical structures of the rat brain containing an ischemic damage focus and penumbra . They fop = 0.048). SNPs rs62278647 and rs2316710 (PTX3) were associated significantly with IS . These correlations for rs62278647 and rs2316710 were found only in women, which suggests a sex-specific association of the PTX3 polymorphism [Interesting results were also obtained by Khrunin et al. in their paper entitled “Examination of Genetic Variants Revealed from a Rat Model of Brain Ischemia in Patients with Ischemic Stroke: A Pilot Study”. The authors were able to correlate the results of gene expression obtained in a rat model of tMCAO with the genomic characteristics of patients with ischemic stroke (IS). Previously, the authors had developed a bioinformatic approach to exploring single-nucleotide polymorphisms (SNPs) in human orthologues of rat genes expressed differentially under conditions of induced brain ischemia . Using tLee et al. present their paper entitled “Association of CYP26C1 Promoter Hypomethylation with Small Vessel Occlusion in Korean Subjects” related to epigenetic studies of stroke. In their study, the authors measured the level of DNA methylation in the CYP26C1 promoter and the 5′ untranslated region of 115 normal subjects and 56 patients in Korea with small-vessel occlusion (SVO) . They foTanaka et al. present their paper entitled “Influence of Renal Impairment and Genetic Subtypes on Warfarin Control in Japanese Patients”, which refers to pharmacogenomic research. It is known that warfarin is an effective means of anticoagulant therapy. However, warfarin has a narrow therapeutic range and shows a wide variation in doses between patients because of numerous environmental and genetic factors that influence warfarin pharmacokinetics and pharmacodynamics. Moreover, the genotypes of vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) can influence therapeutic warfarin doses ,11,12. TFinally, our SI includes an interesting research article by Leira et al. based on the application of bioinformatics methods entitled “Network Protein Interaction in the Link between Stroke and Periodontitis Interplay: A Pilot Bioinformatic Analysis”. In this exploratory study, the authors conducted a protein–protein network interaction (PPI) search with documented encoded proteins for both stroke and periodontitis . Genes oAdditionally, results and prospects for stroke genomics were systematized and discussed in substantial reviews.The first review in our SI entitled “Monogenic Causes of Strokes” by Chojdak-Łukasiewicz et al. reports that monogenic disorders are rare but play significant roles in the causes of strokes, especially in young people. The monogenic causes of stroke are recognizable by key clinical features and radiographic pictures. Genetic tests are expensive but should be part of routine diagnostic procedures in younger patients with cerebrovascular events, especially in the absence of typical vascular risk factors . The mosThe SI also includes a review characterizing one of the examples of ethnic features of stroke genomics. In their review entitled “Genetic and Genomic Epidemiology of Stroke in People of African Ancestry”, Prapiadou et al. describe significant racial/ethnic differences in the incidence, subtype, and prognosis of stroke between people of European and African ancestry, of which only about 50% can be explained by traditional stroke risk factors . HoweverAnother review entitled “The Genetic Landscape of Patent Foramen Ovale: A Systematic Review” by Paolucci et al. will undoubtedly attract attention to our SI. It should be noted that paradoxical embolism through patent foramen ovale (PFO) is an important cause of cryptogenic IS, especially in younger patients. Consistent with this observation, the rate of PFO in siblings of young patients with IS and PFO is three times higher than in siblings of patients without PFO ,17,18. IFinally, the review entitled “Influence of Haptoglobin Polymorphism on Stroke in Sickle Cell Disease Patients” by Edwards et al. is of substantial interest for our SI. This review outlines the current clinical research investigating how the haptoglobin (Hp) genetic polymorphism and stroke occurrence are implicated in sickle cell disease (SCD) pathophysiology . Hp is aIn conclusion, the diversity and quality of the studies presented in this SI indicate the constant advancement of knowledge in the field of genomics of stroke.We hope that our SI will be useful and interesting for readers. Further development of the field of stroke genomics will bring society closer to improving diagnostic, prognostic, and therapeutic measures to combat stroke and related pathologies.


Mental health (MH) service users have increased prevalence of chronic physical conditions such as cardio-respiratory diseases and diabetes. Potentially Preventable Hospitalisations (PPH) for physical health conditions are an indicator of health service access, integration and effectiveness, and are elevated in long term studies of people with MH conditions. We aimed to examine whether PPH rates were elevated in MH service users over a 12-month follow-up period more suitable for routine health indicator reporting. We also examined whether MH service users had increased PPH rates at a younger age, potentially reflecting the younger onset of chronic physical conditions.A population-wide data linkage in New South Wales (NSW), Australia, population 7.8 million. PPH rates in 178 009 people using community MH services in 2016–2017 were compared to population rates. Primary outcomes were crude and age- and disadvantage-standardised annual PPH episode rate (episodes per 100 000 population), PPH day rate  and adjusted incidence rate ratios (AIRR).MH service users had higher rates of PPH admission  and a larger number of hospital days  than other NSW residents due to increased likelihood of admission, more admissions per person and longer length of stay. Increases were greatest for vaccine-preventable conditions , and chronic conditions . The highest number of admissions and relative risks were for respiratory and metabolic conditions, including chronic obstructive airways disease  and diabetic complications . One-quarter of excess potentially preventable bed days in MH service users were due to vaccine-related conditions, including vaccine-preventable respiratory illness. Age-related increases in risk occurred earlier in MH service users, particularly for chronic and vaccine-preventable conditions. PPH rates in MH service users aged 20–29 were similar to population rates of people aged 60 and over. These substantial differences were not explained by socio-economic disadvantage.PPHs for physical health conditions are substantially increased in people with MH conditions. Short term (12-month) PPH rates may be a useful lead indicator of increased physical morbidity and less accessible, integrated or effective health care. High hospitalisation rates for vaccine-preventable respiratory infections and hepatitis underline the importance of vaccination in MH service users and suggests potential benefits of prioritising this group for COVID-19 vaccination. Disadvantage, lifestyle, increased prevalence of chronic illness, medication side effects, reduced help-seeking and the accessibility and quality of health care all contribute to this mortality gap  rates of PPH in MH service users, examining whether increased rates observed in longer-term follow-up studies are also observed over shorter time periods more suitable for routine indicator reporting. Second, to examine the relationship between age and the risk of PPH admission. People with MH conditions have a younger age at onset of risk factors such as obesity and conditions such as cardiovascular disease  state government hospital and community services are provided through 15 geographically organised Local Health Districts and three Speciality Health Networks, which are responsible for physical care  as well as MH care. State government-operated community MH services are organised around geographical catchment areas, are free of charge and can be accessed without referral by a General Practitioner (primary care physician). Private office-based primary and specialist care, private hospital care, and pharmaceuticals are funded or subsidised by the Australian Federal Government with a varying degree of consumer co-payment. Referral by a General Practitioner is required to access subsidised private specialist care. Private hospitals mainly provide non-emergency care (including voluntary MH care) for individuals opting in to private health insurance: in the study period, private hospitals provided 23% of total acute overnight hospital episodes in NSW and 27% of acute overnight hospital days  MH service user status, defined as any contact with state specialist MH services in the preceding 2 years, (ii) age and (iii) socio-economic status of person's area of residence. MH service user status was defined by linkage to state-wide community MH datasets.The study group (MH group) were NSW residents aged 0–100 years who had clinical contact with any NSW government  ambulatory MH service between 1 July 2015 and 30 June 2017. These included face-to-face, telephone or videoconference contacts in community MH centres, home visits, hospital outpatient clinics or emergency departments. Services to non-NSW residents, administrative contacts, case conferences and in-reach services to hospital inpatients were excluded. Age, sex and area of residence were defined at the index contact in the observation period. Primary care, private specialist care and non-government organisation contacts are not available in the dataset.The main outcome was admission to any NSW public or private hospital in 1-year observation period between 1 July 2016 and 30 June 2017 with a primary or secondary diagnosis of a PPH, as defined using Australia's national specification  program, a data linkage examining premature mortality in MH service users. Data were linked by the NSW Centre for Health Record Linkage . Data sets and linkage methods are described elsewhere  any PPH, (ii) three PPH groups  and (iii) 21 individual PPH conditions. For ease of interpretation, chronic conditions were further sub-grouped into cardiovascular, metabolic and respiratory conditions, and acute conditions into acute infections, seizures and other acute conditions. Episodes with multiple PPH diagnoses were counted separately for condition-specific rates but treated as a single episode when calculating overall PPH rates. Age-specific rates were calculated using 5-year bands defined by age on 30 June 2016. Differences in the proportion of people with any PPH were tested using a two-sample test of proportions. Differences in the number of PPH episodes per person and the average length of stay of PPH episodes were compared using Wilcoxon's rank-sum test.Adjusted Incidence Rate Ratios (AIRRs) were calculated by direct standardisation to the NSW non-MH population distributions for age group and for the socioeconomic disadvantage index of the person's area of residence (expressed as a quintile). Disadvantage was measured using the Australian Bureau of Statistics Index of Relative Socioeconomic Disadvantage (IRSD)  PPHs occurring prior to first MH contact in the observation period, (ii) admissions to private hospitals and (iii) PPH with associated MH care.The study was approved by the NSW Population and Health Service Research Ethics Committee  and the Aboriginal Health and Medical Research Council of NSW (Ref 1564/19).The study is overseen by (i) a Steering Committee which includes representation from peak organisations representing NSW health consumers, MH service users and MH carers, and (ii) an Aboriginal Advisory Committee which includes Aboriginal people with lived experience, community organisation, policy and research expertise.et al., A total of 178 009 people had contact with NSW ambulatory MH services in the observation period. Half (50.1%) were male. MH service users were younger than the NSW population: most were aged between 15 and 44 , see Supplementary Table s2. Diagnostic characteristics of our community cohort are described elsewhere: the most common specific diagnoses are affective disorders, psychotic disorders and other MH conditions including anxiety and adjustment disorders , particularly chronic obstructive airways disease . Rates were also significantly increased for metabolic conditions  including diabetic complications  and for cardiovascular conditions . Amongst acute conditions, the highest rate ratios were for seizures and epilepsy , which comprised 12% of total PPH admissions in the MH group but only 5% in the non-MH group.After adjustment for age and disadvantage, MH service users experienced 3.6 (95% CI 3.5–3.6) times the rate of PPH compared to other NSW residents . AIRR weother vaccine-preventable conditions , which includes hepatitis B and C, mumps, herpes zoster, diphtheria and pertussis, as well as for vaccine-preventable pneumonia and influenza  which includes influenza and haemophilus or streptococcal pneumonia.PPH risk was increased for both categories of vaccine-preventable conditions. Risk was elevated for The risk of PPH admission varied with age . Preventable hospital days were increased in most conditions, particularly chronic respiratory conditions , diabetes complications , vaccine-preventable conditions , acute pneumonia  and seizures and epilepsy . The average length of stay was increased for almost all PPH conditions.MH service users had more than five times the number of hospital days per 100 000 population  compared with other NSW residents . Chronicchronic obstructive pulmonary disease, diabetic complications, congestive cardiac failure, cellulitis, seizures and urinary tract infection. Vaccine-preventable conditions contributed nearly one-quarter (24.5%) of excess bed days because of their greater incidence and substantially increased length of stay.MH service users experienced 63 134 days in the hospital due to PPH conditions in 2016–2017; 80% more than the expected number among other NSW residents , excluding PPH admissions to private hospitals significantly increased the gap between MH service users and other NSW residents, because MH service users had fewer PPH admissions in private hospitals. Excluding PPH episodes occurring in specialised MH units, or PPH episodes occurring prior to a person's first community MH contact did not significantly alter the AIRR for PPH episode rates and caused a small but statistically significant reduction in AIRR for PPH days.et al., et al., et al., et al., et al., In the NSW population of nearly 8 million, MH service users had 3–4 times more preventable hospital admissions for physical health care, were admitted at a much younger age and spent substantially longer in hospital for equivalent conditions when compared to people without MH service contact. These findings are likely to reflect several interacting factors. First, rates of medical morbidity are increased in people with MH conditions. Our finding of more than five-fold increases in admission rates for chronic respiratory disease and diabetes complications is consistent with the increased prevalence of these conditions in people with MH conditions (Firth et al., et al., et al., et al., et al., Second, increased preventable admission is likely to reflect health system factors. PPHs are an effective measure of access to primary and specialist care (Parchman and Culler, et al., We found that MH service users had five-fold increases in per capita rates of preventable hospital bed days. Of the total, 80% of bed days for MH service users were excess to those which would be expected if PPH incidence and the average length of stay were the same as for other NSW residents. MH service users are around 2% of the NSW population, but account for around 10% of preventable bed days for chronic respiratory and metabolic conditions and up to 20% of bed days for vaccine-preventable conditions. These findings highlight the significant burden of these preventable hospitalisations for individuals and for the health system. The finding of longer average stays for equivalent conditions underlines the importance of proactive consultation-liaison psychiatry, and integrated physical and MH care in general hospital settings (Oldham higher than in earlier cohorts with longer follow-up periods. Kisely et al. (et al. (The current study examined whether increased PPH rates reported in previous longer-term studies were also observed over a 12-month time period more suitable for routine indicator reporting. Relative rates in the current study were y et al.  examined (et al.  followedet al., The second aim of the current study was to examine the interaction between age and PPH in MH service users. One study has reported a U-shaped relationship between age and PPH rates, finding higher rates of PPH among children, youth and older people (Guo This study uses linked data from routine health collections and therefore shares the limitations and biases of such data sets. In particular, the current dataset is biased towards the identification of people with more acute or severe MH conditions. Each year more than 10% of Australians access a MH service (Australian Institute of Health and Welfare, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., relative risk. However, our findings may not generalise directly to other health systems which use different definitions.Medical comorbidity and premature mortality in MH care is a global problem (Liu et al., et al., et al., et al., Socioeconomic disadvantage influences population PPH rates (Pappas et al., Twelve-month PPH rates appear to be a potentially useful indicator for measuring the personal and health system impacts of increased medical morbidity in MH service users. Collaborative efforts such as the ‘Equally Well’ initiatives in the UK, Australia and New Zealand (National Mental Health Commission,


Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. There is currently no effective treatment, which makes preclinical prediction for AD particularly important  applications.Wang X. et al., focus on subjects with low and high plasma Aβ levels among individual with SCD. They investigate the microstructural changes in white matter (WM) based on diffusion tensor imaging from dataset of Sino Longitudinal Study on Cognitive Decline (SILCODE). Result shows a correlation between WM integrity  and plasma β-amyloid (Aβ) 40 levels rather than Aβ42 in individuals with SCD. This indicates plasma Aβ40 levels may represent a useful biomarker to predict different trajectories of aging in individuals with SCD.The author Qiao et al., analyses the associations between WM disruptions and cognitive declines at the early stage of subcortical vascular cognitive impairment (SVCI). This study concludes the damage of long WM in right hemisphere in the pre-SVCI patients and correlated with declines in executive functions and spatial processing.Another case-control study by Huang et al., uses multi-kernel support vector machine (SVM) to examine whether WM structural networks can be used for screening SCD and aMCI. Their findings promote the development of potential brain imaging markers for the early detection of AD.The study by Yang et al., explore microstructural and cerebral blood flow (CBF) abnormalities in individuals with SCD plus and aMCI. They point out the mean kurtosis of DKI may be used as an early potential neuroimaging biomarker and may be more sensitive than CBF at the very early stage of AD.Based on diffusional kurtosis imaging (DKI) and three-dimensional (3D) arterial spin labeling (ASL), Wu Z. et al., examines group differences in gray matter surface morphometry, including cortical thickness, the gyrification index (GI), and the sulcus depth. The authors aim to track the progression of the disease in different stages of AD, including health controls, early MCIs, late MCIs, and ADs. Based on region-of-interest (ROI) analysis, their study shows that cortical thickness and sulcus depth indices are predominant during AD progression while GI is insensitive. The findings highlight the relevance between gray matter surface morphometry and the stages of AD, laying the foundation for in vivo tracking of AD progression.The paper by Fu et al., extracts gray matter volumes to predict the regional densities in the whole brain in normal control (NC), SCD, Amnestic mild cognitive impairment (aMCI) and AD. In this study, decreased structural covariance and weakened connectivity strength are observed in SCD compared with NC. In addition, increased structural covariance in aMCI and decreased structural covariance in AD are also found. These results provide evidence to the structural disconnection hypothesis in individuals with SCD.The study by Li et al., points out the impairment in spatial navigation (SN) in patients with MCI. They demonstrate that structural connectivity network abnormalities, especially in the frontal and parietal gyri, are associated with a lower SN accuracy, independently of white matter hyper intensities, which providing a new insight into the brain mechanisms associated with SN impairment in MCI.The study by Cui et al., points out different functional activity of the SCD patients with aMCI patients, which suggest SCD may be a separate stage of cognitive decline before aMCI and is helpful to the study of preclinical cognitive decline.The study by Tao et al., further identify individuals with SCD or aMCI from healthy control (HC) and to describe the relationship of pathological changes in these two stages. They conclude that the neural degeneration from SCD to aMCI follows a gradual process, from abnormalities at the nodal level to those at both nodal and network levels.Based on the topological characteristics of the WM network, Chen Q. et al., identifies distinct functional states and explore the reconfiguration functional connectivity (FC) in individuals with SCD. Results indicate that the alterations of dynamic FC may underlie the early cognitive decline in SCD patients and could be served as sensitive neuroimaging biomarkers.The study by Wei et al., discover four interactions among self-reference network (SRN), dorsal attention network (DAN), and salience network (SN) using resting-state fMRI. These results point out that the influence of the SRN in the ultra-early stages of AD is non-negligible.Taking the important role of self-reference processing into account, Xu et al., explores the specific characteristic based on the multimodal brain networks, including individual morphological, structural and functional brain networks. Results highlight the role of cortical-subcortical circuit in individuals with SCD, providing potential biomarkers for the diagnosis and prediction of the preclinical stage of AD.The study by Wu L. et al., investigates the cognitive impairment in individuals with chronic pontine stroke based on voxel-mirrored homotopic connectivity. Results indicate the important role of lingual gyrus and precuneus as ROIs in the early diagnosis of cognitive impairment individuals with chronic pontine stroke.The study by Wang Y. et al., demonstrates that the carotid calcifications are associated with post-stroke cognitive impairment (PSCI). They conclude that the significant role of large vessel atherosclerosis in PSCI should be concerned in future study.The study by Chen Y. et al., concludes that the methylation of peripheral NCAPH2 could be used as a useful peripheral biomarker in the early stage of AD screening. Low levels of NCAPH2 methylation are observed in SCD, and which is independent of the APOE ε4 status. In addition, there is a positive correlation between NCAPH2 methylation levels and the hippocampal volumes in SCD APOE ε4 non-carriers.The study by Dakterzada et al., compares the results of Innotest enzyme-linked immunoassay (ELISA) with two automated methods (Lumipulse and Elecsys). Both Lumipulse and Elecsys methods are highly concordant with clinical diagnoses, and the combination of Lumipulse Ab42 and P-tau has the highest discriminating power. They recommend both automated methods for the measurement of CSF biomarkers.The study by Shi et al., explores whether adenosine receptor 1 (A1 R) is involved in electroacupuncture (EA) pretreatment induced cognitive impairment after focal cerebral ischemia in rats. The results showed that EA pretreatment revered cognitive impairment, improved neurological outcome, and inhibited apoptosis at 24 h after reperfusion. Pretreatment with CCPA (a selective A1 receptor agonist) could imitate the beneficial effects.The study by Lin et al., examines the relationship between spinal cord injury (SCI) and olfactory dysfunction. They point out that the SCI initiates pathological processes, including inflammatory response and impaired neurogenesis. These results provide a basis for pathological mechanisms of early neurodegenerative diseases involving the olfactory bulb and enable early clinical drug intervention.The study by Wu P. et al., proposes the sustained clinical efficacy of unilateral magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy in Chinese patients with ET.Essential tremor (ET) is occasionally associated with a high risk for MCI and dementia. The retrospective study by JJ, YH, and FJ have written this editorial for the Research Topic they have edited. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The study of child and adolescent learning has generally focused on aspects specifically tied to individual academic performance. However, a new emerging perspective is that any “deficit” and/or disability and conversely any achievement is not the result of a single event, such as an isolated reaction, but it is formed, through numerous biosocial contributing variables, during a child's attempt to adapt to learning conditions and settings. The fit between such adaptations and normative criteria  is often associated with labels such as “fulfillment,” “strengths” “resilience” or “weaknesses,” “risk,” “vulnerability” and “disability.”This Research Topic explored the overlapping challenges and themes related to developmental adaptations (as defined above) in the context of formal and informal settings for learning primarily within childhood and adolescence.Jefferies et al. investigated the relationships between the multidimensional constructs of physical literacy and resilience in 227 school Canadian children aged 9–12 years old. They found that resilience was predicted by movement capacity, confidence, and competence, environmental engagement, and overall perceptions of physical literacy. Their research highlights the importance of introducing physical literacy in schools.To start off in this path, Ato et al. examined the impact of temperament on academic achievement and sociometric status in a sample of 295 6–7-year-old Spanish children. Parents completed the Temperament in Middle Childhood Questionnaire, while sociometric status and academic achievement were derived from teachers' reports. Latent profile analysis showed that Children in the “Negative/Undercontrolled” profile were at higher risk for academic failure and peer rejection, while “Sociable/High regulated” showed the reverse pattern. The findings have very important (so far underexplored) implications for ways in which schools could integrate “difficult children.”In a similar vein, Yao et al. examined the association of dopamine-related genes with mental and motor development and gene-environment interaction in 201 preterm and 111 term Taiwanese children, who were followed from 6 to 36 months and were genotyped for 15 single-nucleotide polymorphisms (SNPs) in dopamine-related genes . MAOA SNPs were robustly associated with the mental (but not motor) development scores throughout early childhood in the premature children but not in the term counterparts. This warrants further investigations on whether the MAOA variants could help develop personalized interventions for preterm children.Two contributions focused on early developmental determinants. Firstly, Li et al. examined whether executive function training (EFT) could improve children's emotional competence (EC). Fifty-five 4-year-old Chinese children were assigned to either EFT or no-EFT group. Pre-test vs. post-test training between-and- within-subjects effects were analyzed to quantify improvement. EFT was associated with significantly higher scores on EC and changes in inhibition control and working memory abilities significantly predicted variation in EC. The findings suggest that intervening on inhibition control and working memory abilities via training may improve preschool children's emotional abilities.Considering another early developmental period, Caramia et al. recruited 29 young Italian adolescents to test whether walking with a smartphone increased fall and injuries risk, and to quantify these possible outcomes, participants were asked to walk along a walkway, with and without a concurrent writing task on a smartphone. Concurrency of walking and smartphone use resulted in reduced step length, gait speed and general aspects of gait stability, regardless of experience or frequency of use, suggesting that using the smartphone while walking may determine an increased risk of injury or falls also for young digital natives.At the other end of the spectrum, adult studies have shown that the concurrency of a smartphone-related task and walking can increase instability and risk of injuries. Zhao et al. developed the Brief Haze Weather Health Protection Behavior Assessment Scale-Adolescent Version (BHWHPBAS-AV), and tested its validity and reliability in two randomly selected districts of Baoding, China, and involving 22 middle-school classrooms and 1,025 valid questionnaires. The BHWHPBAS-AV scale showed promising reliability and validity suggesting it may be applied to assess adolescent haze weather health protection behavior, and help school and medical staff administer targeted behavioral and preventative interventions or health education programs.Adopting an approach to prevent air pollution, Grant et al. assessed the cognitive profiles of 360 Canadian adults and children ranging from 7 to 80 years of age with disability in reading alone, mathematics alone and both (comorbidity), with tests widely used in both psychoeducational and neuropsychological batteries. Through a systematic exhaustive review of clinical neuroimaging literature, they mapped the complex set of domain-specific and domain-general impairments shown in the comorbidity of reading and mathematical disabilities to correspondingly plausible neuroanatomical substrates of dyslexia and dyscalculia. According to their hypothetical model, reading-math comorbidity seems due to atypical development of the left angular gyrus. This neuroeducational framework may assist to improve both early prediction and intervention across developmental periods.In a second prevention study, Malboeuf-Hurtubise et al. reported a pilot study based on a new intervention, which combines mindfulness meditation and Philosophy for Children (P4C) activities, with the goal of improving mental health in pre-kindergarten children. Thirty-eight pre-kindergarten Canadian children took part in this study and were randomly allocated to the experimental or wait-list control conditions. Teachers completed pre- and post-intervention questionnaires. Although there were no significant effects, some improvement trends were found for internalized symptoms and hyperactivity. The results partly contradict previous research and suggest that mindfulness and P4C may not be effective intervention for mental health in children. However, the study also suggests a host of other confounding variables that might be responsible for the null findings and should be addressed in future research.Finally, In summary, this Research Topic collection explored how children's preferences, profiles and predispositions are shaped by the social and biological activities that form the background of their everyday living. These papers addressed integrated multidisciplinary issues of education, development and public health, contributing practical examples of viable and sustainable local targeted programs, which, hopefully, may stimulate future research.AD'A wrote the first draft. All authors contributed equally to edit to final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


GBA1, the gene encoding the enzyme glucocerebrosidase. Deficiency of glucocerebrosidase leads to the accumulation of the substrates glucocerebroside and glucosylsphingosine in macrophages and neuronal cells. Variants in GBA1 are a significant genetic risk factor for Define- Parkinson disease (PD)  methods  is a rare autosomal recessive lysosomal storage disorder caused by pathologic variants in GBA1 is located in a gene-rich region on chromosome 1q21 that encompasses seven genes and two pseudogenes within an 85-kb region , non-processed pseudogene, GBAP1 , encoding for part of the mitochondrial outer membrane import complex protein 1, which is transcribed convergently to GBA1 , which now includes over 600 different GBA1 variants with differing predicted clinical significance (https://www.centogene.com/centolsd.html). Many NGS protocols have utilized short-read sequencing, which can provide data at a relatively low cost and high accuracy but may be less reliable in cases where there are structural variants and repetitive or highly homologous regions (Mandelker et al., GBA1, Zampieri et al. initially aligned reads to the whole genome, but missed almost all recombinant alleles, which had aligned preferentially to GBAP1 (Zampieri et al., GBA1 rather than the whole genome, they were able to identify recombinant variants that had initially been false negatives, except for the 55-bp deletion mutation. Alignment against the whole genome did not significantly affect the mapping quality and coverage of missense mutations unrelated to recombination. Care should therefore be taken not only in the library preparation, but also in data analysis steps of NGS pipelines to sequence GBA1.Next-generation sequencing is able to generate vast amounts of sequence data and has been applied to identify variants in GBA1 variants using the Oxford Nanopore MinION (Leija-Salazar et al., NciI. Another study aimed to expand upon this protocol by refining and applying it to the discovery of GBA1 variants in a PD longitudinal cohort from New Zealand (Graham et al., GBA1 and updated the software pipeline, improving accuracy and reducing the computational workload, but were unable to detect any recombinant gene conversion alleles or deletions of >50 bp.The introduction of long-read sequencing technology in recent years addressed some limitations of short-read sequencing (Goodwin et al., GBA1 is complicated by complex gene-pseudogene rearrangements and recombination. Recombinant alleles make up a significant proportion of GBA1 mutations and sites of recombination events have been identified between intron 2 to exon 11 (Hruska et al., GBA1 and its pseudogene, there is an increased likelihood of both reciprocal and non-reciprocal recombination (Tayebi et al., NciI. In this allele, the site of crossover of chromosomal mispairing between gene and pseudogene occurs within intron 9 and continues to the 3'-UTR of the gene, introducing three exon 10 nucleotide mismatches (Latham et al., RecTL, covers the pseudogene sequence from intron 8 or the beginning of exon 9 [GBAP1 (Martinez-Arias et al., MTX and its pseudogene as well (Tayebi et al., GBA1 alleles (Velayati et al., Accurate and comprehensive NGS analysis of GBA1 gene rearrangements cannot be sufficiently captured using most current NGS methods. Several recent studies using NGS technology without Sanger sequencing validation have not reported the presence of recombinant alleles, including a recent study performed on more than 3,000 PD cases (den Heijer et al., The complexity of de novo or germline mutations on the maternal allele (Saranjam et al., GBA1 and S78L in MPZ (Benko et al., GBA1 mutation on the same allele (Hassan et al., GBA1 screening, and for now, Sanger sequencing should be used for the most accurate genotyping.Gaucher disease is an autosomal recessive disorder that usually results from the inheritance of a mutant allele from each parent. Increasing evidence suggests this may not always be the case, and that there are important exceptions to the traditional Mendelian pattern of inheritance, such as new mutations or uniparental disomy (Nakka et al., GBA1 in many Parkinson disease NGS analyses, it is important to consider the effects of the nearby homologous pseudogene. Recombinant alleles in GBA1 have been identified in patients with GD and with PD that might be missed when relying on NGS analysis alone without Sanger sequencing validation.Next-generation sequencing allows for unbiased simultaneous analysis of many genes. In addition, it makes it more feasible to analyze specific genes in larger cohorts for the study of common diseases like Parkinson disease. With the inclusion of GBA1 confirmed by Sanger sequencing. In addition, there is evidence to suggest that the choice of polymerase used could be a factor in the accuracy of NGS variant identification. A recent study performed a large-scale screening of GBA1 based on an NGS protocol and found a significant number of false negatives due to a polymerase-dependent allelic imbalance (den Heijer et al., Challenges exist in short-read NGS methods for sequencing highly homologous regions. The shorter reads cannot be mapped uniquely to the reference genome, especially in cases where there are recombinant alleles aligning to the homologous region. A computational custom scaffold-based approach was recently introduced to improve the detection and phasing of targeted complex variants using short reads (Zeng et al., GBA1 from their pseudogenes. An additional advantage is the ability to phase mutations and assign haplotypes. It can also detect intronic SNPs. There are still some limitations, including high costs, low throughput, and high per-base error rates. Long-read NGS also has a limited ability to accurately resolve homopolymers and to detect small insertions and deletions. Importantly, it is still unable to consistently detect recombinant alleles.Long-read NGS has many advantages, one of which is an improved ability to discriminate functional genes such as GBA1 variants and recombination remains Sanger sequencing. Without validation by Sanger sequencing, the frequencies of GBA1 variants based on NGS analysis may be underestimated, particularly for complex recombinant alleles. Real-time PCR can also be used to identify recombinant alleles (Velayati et al., GBA1 NGS analysis, it is still currently limited in its capacity to recognize recombinant alleles. The shortcomings identified will likely also be pertinent for the analysis of other genes with highly homologous pseudogenes. As sequencing technology continues to rapidly progress, we will likely continue to see improved detection of GBA1 variants. This has exciting potential for clinical diagnostics and studies of large patient cohorts.The most accurate method for detecting all EW: drafted the manuscript and figure. NT: organized the topic, reviewed the literature, and edited the manuscript. ES: conceived of the topic and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Motoric Cognitive Risk (MCR) syndrome is a clinical syndrome combining slow walking speed and subjective cognitive complaints (SCC) that was first reported by Verghese et al. in 2013 [Recently, we reported that MCR is associated with anxio-depressive disorders and depression (ADDD) in a cross-section of a large population-based cohort known as “The Canadian Longitudinal Study on Aging” . We demoThe risk of major neurocognitive disorders in individuals with MCR is more than twice that of those without MCR . FurtherIn addition to MCR, depression has been independently associated with an increased risk of major neurocognitive disorders . In indi


Cancer research in the field of Computational Systems Biology attempts to address questions that will advance current knowledge in the mechanisms of cancer progression or treatment resistance. By analyzing multi-omics data and developing a predictive mathematical and/or computational model of an unknown biological system, we can systematically understand 1) the mechanisms that tie altered gene expression and downstream molecular mechanisms to functional cancer phenotypes ; 2) and/Artificial Intelligence (AI) Optimized Systems Modeling for the Deeper Understanding of Human Cancers” in Frontiers in Bioengineering and Biotechnology, and Frontiers in Genetics aims to provide an international forum for:1) bringing together the greatest research efforts in cancer-specific molecular/network signature identification by integrating multi-omics/multi-level data;etc., to provide novel ideas and solutions in mathematical modeling for tumor growth, drug resistance, and targeting effect prediction;2) exploring future-generation interesting and practical biomedical applications in AI, machine learning, big data sciences, knowledge-based system, 3) addressing the real-world challenges in the fields of AI-based patient diagnosis or disease progression prediction by utilizing modern machine learning or statistical strategies, and produce a more reliable and promising application environment to develop those technologies.This special issue entitled “etc. The final acceptance rate is 50% with 18 accepted papers in this special issue. The summaries of these papers are outlined below.1) New bioinformatic approaches to Identify key molecular/network signatures for precision diagnosis or treatment of cancersSubmission for this special issue started from May 2020 and closed in Oct 2020. In nearly one and half years, we received in total 36 paper submissions. All submitted manuscripts had gone through at least two rounds of revision with reviewers in the related fields, including bioinformatics, computational biology, machine learning, and clinical study, Identification of signatures of prognosis prediction for melanoma using a hypoxia score” by Shou et al. The authors developed a computational method to identify the gene signatures of melanoma in hypoxic condition for prognosis prediction.In the article entitled “Identifying hypoxia characteristics to stratify prognosis and assess the tumor immune microenvironment in renal cell carcinoma” by Zhang et al. The authors established a hypoxia-related risk model to predict the prognosis of patients.In the article entitled “Prediction of Radiosensitivity in Head and Neck Squamous Cell Carcinoma Based on Multiple Omics Data” by Liu et al. The authors identified 12-gene signature based on multiple omics data achieved the best ability for predicting radiosensitivity in Head and Neck Squamous Cell.In the article entitled “An Effective Graph Clustering Method to Identify Cancer Driver Modules” by Zhang et al. The authors proposed a graph clustering method, called “MCLCluster”, to identity cancer driver modules that drive cancer progression.In the article entitled “Exploring the differential expression and prognostic significance of the COL11A1 gene in human colorectal carcinoma: an integrated bioinformatics approach” by Patra et al. The authors developed an integrated bioinformatics approach to reveal the COL11A1 gene as a prognostic biomarker in colorectal carcinoma.In the article entitled “MicroRNA-126 Modulates Palmitate-induced Migration in HUVECs by Downregulating Myosin Light Chain Kinase via the ERK/MAPK Pathway” by Zhu et al. The authors evaluated the effects of miR-126 on the cell migration and uncovered the underlying mechanism in HUVECs treated with palmitate.In the article entitled “Integrated analysis of DEAD‐box helicase 56: a potential oncogene in osteosarcoma” by Zhu et al. The authors set up a novel integrated analysis protocol and found that DDX56 is a potential therapeutic target for the treatment of osteosarcoma.In the article entitled “A machine learning approach for tracing tumor original sites with gene expression profiles” by Liang et al. The authors developed a machine learning approach by integrating random forest and Naive Bayesian, to predict the primary origin sites of tumors.In the article entitled “A deep learning framework to predict tumor tissue-of-origin based on copy number variation” by Liang et al. The authors proposed a deep learning framework composed of an autoencoder (AE) and a convolution neural network (CNN) to predict the primary origin sites of tumors.In the article entitled “TOOme: a novel computational framework to infer cancer tissue-of-origin by integrating both gene mutation and expression” by He et al. The authors integrated somatic mutation and gene expressions t infer the primary original sites of tumor and obtained a great accuracy.2) New studies of clinical informatics for speeding up the development of cancer diagnosisIn the article entitled “Diagnosis of cervical cancer with parametrial invasion on whole-tumor dynamic contrast-enhanced magnetic resonance imaging combined with whole-lesion texture analysis based on T2-weighted images” by Li et al. The authors integrated DCE-MRI images and texture analysis for diagnosis cervical cancer.In the article entitled “Predictive value of the texture analysis of enhanced computed tomographic images for preoperative pancreatic carcinoma differentiation” by Zhang et al. The authors extracted 396 features from patient CT images and selected the optimal feature subset to predict the pathological degree of differentiation of pancreatic carcinoma.In the article entitled “RA-UNet: A hybrid deep attention-aware network to extract liver and tumor in CT scans” by Jin et al. The authors developed a 3D network model, RA-UNet, to precisely extract the liver region and segment tumors from the liver. Testing on public datasets show that the proposed architecture obtains competitive results.In the article entitled “Classification of Infected Necrotizing Pancreatitis for Surgery within or beyond Four Weeks Using Machine Learning” by Lan et al. The authors applied machine learning models to predict the optimal timing of surgical intervention and identified the key factors associated with surgical timing for infected necrotizing pancreatitis.In the article entitled “Prediction of Proximal Junctional Kyphosis after Posterior Scoliosis Surgery with Machine Learning in the Lenke 5 Adolescent Idiopathic Scoliosis Patient” by Peng et al. The authors developed a machine learning model for proximal junctional kyphosis (PJK) prognostication in Lenke 5 adolescent idiopathic scoliosis (AIS) patients undergoing long posterior instrumentation and fusion surgery.In the article entitled “A New Method Based on CEEMD Combined with Iterative Feature Reduction for Aided Diagnosis of Epileptic EEG” by Peng et al. The authors proposed a computational method based on complementary ensemble empirical mode decomposition (CEEMD) combined with iterative feature reduction for aided diagnosis of epileptic EEG.3) New strategies for optimizing the data preprocessing and quality controlIn the article entitled “Assessing the impact of data preprocessing on analyzing next generation sequencing data” by He et al. The authors compared commonly used data preprocessing software and found differences in the detection of hotspot mutations and HLA typing. They also explained the impact of data preprocessing steps on downstream data analysis results.In the article entitled “RF-PCA: A New Solution for Rapid Identification of Breast Cancer Categorical Data Based on Attribute Selection and Feature Extraction” by Bian et al. The authors developed a hybrid model RF-PCA, which significantly reduce the time required for the classification, but also improved the accuracy.In the article entitled “The guest editors would like to thank all authors submitting their valuable works to this special section of Frontiers in Bioengineering and Biotechnology, Frontiers in Genetics, as well as all peer-reviewers for their great effort reviewing the submitted articles, providing constructive comments and suggestions and assisting the editors reaching the final decision. Special thanks will be sent to the editor-in-chief (EIC), Ranieri Cancedda and José AG Agúndez, for their precious time and valuable instructions that help us prepare and finalize this special issue.