The atrial fibrillation better care (ABC) pathway is a simple, comprehensive framework that facilitates provision of integrated care for atrial fibrillation (AF) patients.We evaluated management of AF patients in a secondary prevention cohort using the ABC pathway and examined the impact of ABC adherence on clinical outcomes.The Chinese Patients with Atrial Fibrillation registry is a prospective registry conducted in 44 sites across China between October 2014 and December 2018. The primary outcome was the composite of all‐cause mortality/any thromboembolism (TE), all‐cause death, any TE and major bleeding at 1 year.p = .004).Of the 6420 patients, 1588 (24.7%) had a prior stroke or transient ischemic attack and were identified as the secondary prevention cohort. After excluding 793 patients due to insufficient data, 358 (22.5%) were ABC compliant and 437 (27.5%) ABC noncompliant. ABC adherence was associated with a significantly lower risk of the composite outcome of all‐cause death/TE, odds ratio (OR) 0.28  and all‐cause death, OR 0.29 (95% CI: 0.09–0.90). Significant differences were not observed for TE, OR 0.27 (95% CI: 0.06–1.27) and major bleeding, OR 2.09 (95% CI: 0.55–7.97). Age and prior major bleeding were significant predictors of ABC noncompliance. Health‐related quality of life (QOL) was higher in the ABC compliant group versus the noncompliant group (EQ score 0.83 ± 0.17 vs. 0.78 ± 0.20; ABC pathway adherence in secondary prevention AF patients was associated with a significantly lower risk of the composite outcome of all‐cause death/TE and all‐cause death, as well as better health‐related QOL.  AF confers a fivefold increase in the risk of ischemic stroke, while a history of stroke or transient ischemic attack (TIA), alongside AF, is associated with 2.5‐fold risk of a subsequent stroke.Given the high recurrence of stroke in AF and the likelihood of a debilitating cerebrovascular event that risks further deterioration, secondary prevention is as crucial and should be a vital element of AF management. However, this carries less emphasis in the literature, with studies specifically focusing on AF patients with previous TIAs/strokes being limited, and little indication of the long‐term clinical outcomes. In a small study by Hayden et al. only 39.2% of AF patients who had ischemic strokes were still alive after 5 years, with a quarter of patients requiring nursing homes and 21.5% having a 5‐year stroke recurrence rate, indicating an extremely poor prognosis and the need for effective measures to ameliorate this.Recently, the atrial fibrillation better care (ABC) pathway was introduced as a simple yet comprehensive clinical tool to facilitate provision of integrated care for AF patients, addressing their risk of stroke, symptoms, and cardiovascular risk factors.2The protocol of the Optimal Thromboprophylaxis in Elderly Chinese Patients with Atrial Fibrillation (ChiOTEAF) registry has been previously described.Follow‐up visits were performed at 6 and 12 months and then annually for the next 2 years. Data were collected by local investigators at enrolment and follow‐up visits (including patient visits and/or chart reviews and/or telephone follow‐up) and recorded in an electronic database.The registry was approved by the Central Medical Ethics Committee of Chinese PLA General Hospital, Beijing, China  and local institutional review boards.2.1ABC adherent when all three criteria (A+B+C) were achieved.The ABC pathway was retrospectively evaluated according to its original definition: patients were considered to have fulfilled the “A” criterion if properly treated with oral anticoagulants (OACs) according to their thromboembolic (TE) risk; “B” criterion if symptoms were adequately controlled, defined by an European Heart Rhythm Association (EHRA) score of I or II (no symptoms or mild symptoms) at the baseline visit; and “C” criterion if they had disease‐specific treatment(s) of any cardiovascular risk factors at baseline. We considered management as guideline‐adherent if the following were true: (i) angiotensin‐converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARB), calcium channel inhibitors, diuretics, beta‐blockers for hypertension; (ii) ACE inhibitors/ARB, beta‐blockers, and statins for coronary artery disease; (iii) statins for peripheral artery disease; (iv) statins for previous ischemic stroke; (v) ACE inhibitors/ARB and beta‐blockers for heart failure; (vi) insulin or oral antidiabetics for diabetes mellitus; and (vii) statins for lipid disorders. Patients were considered 2DS2‐VASc and HAS‐BLED scores were used to assess TE and bleeding risks respectively. Bleeding  events were categorized based on the International Society on Thrombosis and Haemostasis definition.Other variables and their definitions matched the EURObservational Research Programme Atrial Fibrillation Long‐term General Registry.2.2The primary objective of this analysis was to evaluate the impact of ABC pathway on clinical outcomes at 1 year in a secondary prevention cohort of AF patients with data available to assess ABC management. Endpoints of interest were the composite outcome of all‐cause death/any TE event , all‐cause death, TE events, and major bleeding.Secondary objectives were to (i) evaluate the impact of the ABC pathway on clinical outcomes compared with the overall secondary prevention cohort and (ii) identify potential predictors of ABC‐adherent management.2.3t‐test or the Mann–Whitney U‐test (based on distribution). Categorical variables were expressed as counts and percentages; between‐group comparisons were made by chi‐squared test or Fisher's exact test. QOL was assessed using the EQ summary index , estimated from the EQ‐5D‐5L value set for China.Continuous variables were reported as mean ± standard deviation; between‐group comparisons were made using the Student's p‐values. p < .05 was considered statistically significant. Statistical analysis was performed using SPSS® version 24 (IBM Corp.).Logistic regression analysis evaluated the association between the degree of ABC compliance and clinical outcomes, adjusted for clinically significant variables . For the secondary objective, sensitivity analysis for the overall secondary prevention cohort was performed. Finally, a logistic univariate regression analysis was used to assess the predictors of the ABC compliance; all the significant variables were included in a multivariate regression model. Results were expressed as odds ratios (ORs), 95% confidence intervals (CIs), and 32DS2VASc score of 5.3 ± 1.5). Baseline characteristics are reported in Table p < .001), with a lower prevalence of chronic kidney disease , chronic obstructive pulmonary disease , dementia , and prior major bleeding  compared with the ABC noncompliant patients.The ChiOTEAF registry enrolled 7077 patients, of which 657 (9.3%) were lost to follow‐up at 1 year . Health‐related QOL was also higher in this group compared with the noncompliant group , but no significant differences in EHRA scores were found.All patients in the ABC group were treated with an OAC as opposed to the ABC noncompliant group where only 13.7% were treated with an OAC and 63.2% were treated with an antiplatelet. In the ABC group, a higher proportion of patients had prior AF ablation  and all‐cause death (1.1% vs. 5.5% p = .001). Odds of the composite outcome  and all‐cause death  were significantly lower in ABC‐managed patients. No statistically significant differences were observed in the incidence of TE and major bleeding events  and excluded (n = 793) patients (Table p < .001) with a lower prevalence of comorbidities, for example, heart failure , chronic kidney disease , chronic obstructive pulmonary disease , dementia , and had a higher uptake of OACs  and AF ablation  compared with the excluded patients.When we compared baseline characteristics between included , all‐cause death , TE , and major bleeding  was observed in the ABC cohort during the 1‐year follow‐up.A lower incidence of the composite outcome  prior AF ablation  was strongly associated with ABC pathway compliance, whereas (ii) older age  and prior major bleeding  were independently associated with lower odds of ABC compliance Table .4In this study which evaluated the impact of the ABC pathway on a secondary prevention cohort of AF patients, we found that ABC adherence was associated with a (i) 72% reduction in the odds of the composite outcome encompassing all‐cause death and any TE, (ii) significant reduction in all‐cause death , and (iii) higher health‐related QOL compared with ABC nonadherence. These findings advocate the adoption of an integrated care approach such as the ABC pathway for management of this high‐risk group.To our knowledge, this is the first study to evaluate the efficacy of the ABC pathway in a secondary prevention AF cohort. Although the ABC pathway has been validated and consistently demonstrated cardiovascular and mortality benefits in several AF populations, it has not specifically been evaluated in AF patients with previous strokes or TIAs.2DS2VASc score of 5.3 ± 1.5, yet only 45% were managed using the ABC approach. This is consistent with, if not better than, existing studies that indicate that the ABC pathway is followed in just one in five AF patients.2DS2VASc and HAS‐BLED scores. Arguably, it is the higher risk patients who stand to achieve the most benefit from appropriate risk reduction measures.Our study comprised a population with a mean CHAOur analysis demonstrated that ABC noncompliance was strongly influenced by age and prior major bleeding, when existing evidence suggests there is no significant increase in the OAC‐associated recurrent bleeding risk once causative factors have been addressed, and potentially with non‐vitamin K antagonists (VKAs) compared to VKAs.In the ABC noncompliant group, 29.9% were not prescribed an OAC and 63.2% were prescribed aspirin. While the latter may be perceived as a “less risky” substitute for anticoagulation, it is possible that the aspirin was prescribed for coronary artery disease which was highly prevalent in this group. In any case, with the ample evidence demonstrating that aspirin confers a similar or higher bleeding risk compared to OACs without the protective effects against strokes, it can be inferred that a significant proportion of these patients would have been able to tolerate anticoagulation.ABC pathway adherence was associated with a significant reduction in the risk of composite outcome of all‐cause death and TE, primarily driven by the reduction in all‐cause death. This is consistent with existing studies that have evaluated performance of the ABC pathway, demonstrating not just a reduction in all‐cause mortality but also other outcomes such as TE, ischemic stroke and major bleeding.Hence, we conducted an exploratory analysis comparing outcomes between the ABC compliant group and the overall cohort comprising ABC noncompliant patients and those whose ABC compliance status could not be fully evaluated. Outcome events were larger in number, albeit still small, and reflected findings from the primary analysis. In the study by Wang et al. a subgroup analysis of patients with previous strokes or TIAs demonstrated a 55% ABC compliance rate with a nonsignificant reduction in all‐cause death, hazard ratio 0.68 (95% CI: 0.47–1.00), bearing in mind the small cohort size.ABC compliance has been associated with a reduction in both the TE and bleeding risks.4.1Although the ChiOTEAF registry was prospective because it was not specifically designed to examine ABC pathway, our analysis was conducted retrospectively in accordance with the published definitions for each of the components.5ABC pathway adherence in the high‐risk secondary prevention AF cohort was associated with a significantly lower risk of the composite outcome of all‐cause death/TE and all‐cause death, as well as better health‐related QOL.This paper has not been submitted for publication to any other journal. All authors have made a significant contribution and have read and approved the final draft. Ameenathul M. Fawzy, Agnieszka Kotalczyk, and Yutao Guo contributed equally to design the study, interpreted the data, and drafted the manuscript (joint first authors). Yutang Wang and Gregory Y.H. Lip contributed in the interpretation of data and revised the manuscript critically for important intellectual content (joint senior authors).The study was supported by Beijing Natural Science Foundation, China (Z141100002114050), and Chinese Military Health Care (17BJZ08).Gregory Y.H. Lip: Consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, and Daiichi‐Sankyo. No fees are received personally. The other authors have no conflict of interest.This study was performed in line with the principles of the Declaration of Helsinki. Ethics approval was granted by the Central Medical Ethic Committee of Chinese PLA General Hospital .Written informed consent was obtained from all individual participants included in the study.Table S1.Table S2.ChiOTEAF Registry InvestigatorsClick here for additional data file.


Aberrantly expressed circular RNAs (circRNAs) have been detected in many types of tumors. Hence, they are currently investigated as candidate biomarkers for diagnostic and potential targets for therapy in cancers. The objective of this study was to assess the expression profile of circRNA in lung adenocarcinoma (LUAD).This study included 14 pairs of postoperative lung adenocarcinoma specimens, including cancer tissues and matched adjacent tissues. Second‐generation sequencing was applied to the specimens to determine the circRNA expression in them among the 5242 distinct circRNAs detected.We identified a total of 18 significantly dysregulated circRNAs in the LUAD tissues: upregulation in four and downregulation in 14. ROC (The receiver operating characteristic curve) further suggested that hsa_circ_0120106, has_circ_0007342, has_circ_0005937, and circRNA_0000826 could potentially be used as biomarkers in the diagnosis of LUAD. Furthermore, study of the circRNA–microRNA (miRNA)–messenger RNA (mRNA) revealed interactions between the 18 dysregulated circRNA and several cancer‐related miRNAs. Finally, a further Kyoto Encyclopedia of Genes and Genomes analysis showed that the cell cycle phase transition, p53 signaling pathway, AMP‐activated protein kinase (AMPK) relative signaling pathway, and so on were key putative pathways in the process of LUAD.These findings demonstrated the correlation between abnormality in circRNA expression and LUAD, which lays the foundation of making CircRNAs candidate biomarkers in the diagnosis of LUAD. CeRNA regulating network was identified from 14 pairs of postoperative lung adenocarcinoma by RNA‐seq analysis Lung cancer has the highest morbidity and mortality among malignant tumors.Circular RNA (circRNAs) is the third largest family of noncoding RNA after microRNAs (miRNAs) and long non‐coding RNA (lncRNAs). They are characterized by a noncovalent closed‐loop structure at the 3′ and 5′ ends, which leads to significant tolerance to exonucleaseTo our knowledge, this study collected the largest number of clinical specimens for the detection of the expression of circRNA in lung cancer and adjacent tissues. In this study, we obtained the differential expression of circRNAs in tissue samples of LUAD tissues and nontumor tissues through high‐throughput sequencing and bioinformatics analysis. We established that chr2|43 973 004|43 992 865|+hsa_circ_0120106, has_circ_0007342, has_circ_0005937, and circRNA_0000826 are promising biomarkers for LUAD.2 immediately on collection. Among the 18 pairs of specimens, four pairs were excluded because of significant RNA degradation that meant they did not meet the requirements. The remaining 14 pairs of specimens then underwent second‐generation sequencing. To verify the result, another 10 pairs of specimens were tested by real‐time qPCR. All the LUAD specimens were subject to histopathological examination in parallel with the aforementioned molecular biological study . This study was approved by the Ethics Committee of the Affiliated Hospital of Guangdong Medical University, and each participant signed an informed consent form.Samples were collected from patients who were diagnosed with LUAD and were treated with radical resection in the department of thoracic surgery at the Affiliated Hospital of Guangdong Medical University from October 2019 to December 2019. Before admission, none of these patients had been treated with any other cancer therapy. From each patient, a pair of specimens was collected, a LUAD tissue specimen and one from an adjacent non‐neoplastic tissue. The specimens were fresh frozen and stored in liquid NAccording to the characteristics of the biological sample, we first extracted all the transcribed RNA of the biological sample, and then selected an appropriate method for sample quality evaluation. Qualified samples were subjected to ribosomal removal, reverse transcription, library construction, and sequencing. The RNA was interrupted and the first strand was synthesized by reverse transcription with random primers. In the second strand synthesis, deoxyuridine 5’‐triphosphate (dUTP) was used instead of deoxythymidine triphosphate (dTTP). After the end repair, Adenine was added to connect the connector. The second strand containing U was then removed under the action of the USER enzyme, leaving only one strand, and PCR amplification was performed on the first strand. The RNA‐seq with chain‐specific libraries has such data characteristics after on‐machine sequencing: read 1 measuring the antisense strand and read 2 measuring the sense strand. After the library was qualified, illumina MiSeq/NextSeq/HiSeq sequencing was performed after pooling the different libraries according to the requirements of effective concentration and target data volume.t‐test between two groups.A high‐throughput sequencer (Illumina HiSeq 4000) gave the paired‐end reads, quality controlled by Q30. The Spliced Transcripts Alignment to a Reference (STAR) software aligned the reads to the reference genome/transcriptome. CircRNAs were identified and recorded with DCC software. The identified circRNAs were then annotated based entries retrieved from databases (CircBase and circ2Trait). Differentially expressed circRNAs were identified by Student's n = 14 pairs) were used as templates to synthesize Complementary DNA (cDNA) with a reverse transcriptase according to the manufacture’s instructions. circRNA expression was measured using qPCR . An ABI 7300 Real Time PCR System (Applied Biosystems) was used to perform the PCR following the protocol 1× 2‐min cycle at 50°C, 1× 10‐min cycle at 95°C, 40× 15‐s cycle at 95°C, and 1 min at 60°C. β‐actin served as a control. PCR was conducted three times on each sample.The circRNA extracted from the LUAD and matching normal tissues . Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for target genes of miRNAs were performed using Metascape.The circRNA–miRNA and miRNA–mRNA networks were combined to obtain the circRNA–miRNA–target genes network as a ceRNA network.t‐test at the 5% level of significance was used to determine the significance for differences in circRNA expression. Statistical analysis was carried out using SPSS and Microsoft Excel.Relative circRNA expression was calculated using the 2^‐(∆∆Ct) method. Student's p adjust was less than 0.05. The expression levels of hsa_circ_0000264, chr20|57 574 397|57 574 864|‐, hsa_circ_0000907, and hsa_circ_0001610 in LUAD patients were upregulated, while the expression levels of chr4|106 832 305|106 832 889|+, hsa_circ_0120106, hsa_circ_0007879, chr10|97 141 441|97 170 534|‐, hsa_circ_0013048, chr22|43 435 785|43 442 579|‐, hsa_circ_0003176, hsa_circ_0002587, has_circ_0005937, hsa_circ_0005941, chr2|167 304 121|167 328 955|‐, hsa_circ_0072309, hsa_circ_0001640, and hsa_circ_0007342 in LUAD patients were downregulated. Since hsa_circ_0003176 and hsa_circ_0002587 have the same gene name and gene ID, subsequent analysis will classify these as circRNAs.To analyze the expression of circRNA in LUAD and explore the potential role of new circRNA biomarkers in the disease diagnosis and prognosis, we performed second‐generation sequencing on our specimens. A total of 5241 circRNAs were detected  regularization to test this idea. Using only seven out of the 18 differentially expressed genes, we were able to achieve 100% prediction accuracy with AUC（Area Under roc Curve） = 1. The seven genes included one gene upregulated in a tumor and the others all downregulated in matched normal samples. Furthermore, we examined the potential of using individual genes as diagnosis markers by conducting receiver operating characteristic (ROC) curve analysis for single genes. Four of the 18 individual genes exhibited AUC > 0.9, suggesting the potential to use single genes for diagnosis. In the ROC curve Figure , the AUCConsidering that the ROC has significant specificity and is clinically relevant, we focused on the circRNAs of AUCs higher than 0.9. From the list in Supporting Information Table In addition, Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) and genome of path analysis showed that target genes that were related to this circRNA signature participated in various biological processes, including receptor complex, cytoplasmic region, and cortical cytoskeleton cancer‐related pathways Figure . The cirPrevious works have established that circRNA regulates gene expression via a variety of mechanisms, such as inhibiting miRNAs by absorbing them. We identified and ranked miRNAs that bind to LUAD‐related circRNAs. Circos plots drawing the predicted binding relationship between circRNA and miRNA are shown in Figure p < 0.05) . IGF2BP3 may therefore be an oncogene and potential prognostic biomarker of LUAD.In the ceRNA network, we enriched many functions, and the mRNA pathways were associated with LUAD in GO and KEGG pathway analyses (Supporting Information Table In this study, we performed high‐throughput sequencing on specimens of patient tissues and carried out bioinformatics analysis on the sequencing data. We discovered several circRNAs that are abnormally expressed in LUAD tissues, and these circRNAs in turn contribute to carcinogenesis via interaction with miRNAs. Consequently, this study provides promising diagnostic markers and potential therapeutic targets, and lays the foundation for the future study of LUAD.This project was a retrospective study. Data were obtained by collecting tissue specimens and clinical pathological characteristics of patients who had undergone surgical resection. It did not require follow‐up of patients or direct contact with patients, and without personal privacy of patients. The collected data was de‐informatized and the subjects can no longer be found. The collected data was only used for statistical analysis and publication of papers, and did not involve personal privacy or commercial interests.All authors gave consent for the publication of manuscript.W.S. and Z.Y. conceived the project and designed the experiments. Y.C., X.H., X.H., Z.L., H.Z., B.L., J.H., and Y.X. performed the experiments. W.S., H.Y., and L.W. wrote the manuscript. Y.S., L.Z., D.Z., and Z.L. analyzed the data. J.H. supervised this work. All authors read and approved the final manuscript.The authors declare that they have no competing interests.Table S1. A total number of 5,241 circRNAs were detected in the specimens by second‐generation sequencing.Click here for additional data file.Table S2. Comparing to adjacent noncancerous tissues, LUAD tissues show upregulation of 4 of these circRNAs and downregulation of the other 14.Click here for additional data file.Table S3. A total of 217 target genes were screened.Click here for additional data file.Table S4. The results suggest that target genes are closely related to cell cycle, p53 signaling pathway, AMPK signaling pathway, and so on.Click here for additional data file.


The purpose of this study was to clarify the dentato‐rubro‐thalamic (DRT) pathway in action tremor in comparison to normal controls (NC) and disease controls  by using multi‐modality magnetic resonance imaging (MRI).This study included 40 essential tremor (ET) patients, 57 Parkinson's disease (PD) patients , and 41 NC. We used multi‐modality MRI to comprehensively assess major nuclei and fiber tracts of the DRT pathway, which included decussating DRT tract (d‐DRTT) and non‐decussating DRT tract (nd‐DRTT), and compared the differences in DRT pathway components between action and rest tremor.Bilateral dentate nucleus (DN) in the ET group had excessive iron deposition compared with the NC group. Compared with the NC group, significantly decreased mean diffusivity and radial diffusivity were observed in the left nd‐DRTT in the ET group, which were negatively correlated with tremor severity. No significant difference in each component of the DRT pathway was observed between the PD subgroup or the PD and NC.Aberrant changes in the DRT pathway may be specific to action tremor and were indicating that action tremor may be related to pathological overactivation of the DRT pathway. The DRT pathway is documented as a potentially promising underpinning for action tremor, but the comprehensive study of DRT pathway in action tremor is insufficient. This study discovers that aberrant changes in the DRT pathway may be specific to action tremor and were indicating that action tremor may be related to pathological overactivation of the DRT pathway. The most studied component of the DRT pathway is the DRT tract (DRTT), which can be robustly tracked by diffusion tensor imaging (DTI), suggesting abnormal changes in DRTT in patients with action tremor.To solve the above problems, we comprehensively quantified the components of the DRT pathway by multi‐modality MRI to investigate the role of the DRT pathway in action tremor, including quantifying the iron deposition and volume changes in nuclear in the pathway using QSM and T1‐weighted images and obtaining the diffusion parameters of DRTT using DTI. In addition, to confirm whether changes in the DRT pathway are specific to action tremor, we also included patients with rest tremor—reflecting the effect of rest tremor by comparing between subgroups of PD patients—to see whether the changes in the DRT pathway are consistent between the two types of tremor.22.1www.tremorresearchgroup.org) to evaluate the severity of ET, with higher scores representing more severe symptoms. And the Hoehn–Yahr stages are currently a relatively well‐recognized PD staging system, with a total of 0–5 stages, with severity increasing with level.This research was approved by the Medical Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine. All the ET and PD patients were recruited from the neurological clinics in the Second Affiliated Hospital of Zhejiang University School of Medicine, while the normal controls (NC) were recruited from the social community in Hangzhou, China. All of them participated in this study from August 2014 to November 2020, and signed informed consent form. Each patient was diagnosed by an experienced neurologist based on the following criteria: ET diagnosis based on the Movement Disorders Society Statement,Sixty ET patients, 142 PD patients, and 50 NC patients were initially recruited in the study. According to the following exclusion criteria, 9 ET, 37 PD, and 9 NC were excluded: (1) left‐handed or double‐handed; (2) history of neurologic or psychiatric disorders ; (3) significant cognitive decline ;nET = 11; Figure n = 43) and PD without rest tremor (PD‐WT) .In order to specifically study the role of action tremor, we further screened ET patients without rest tremor of both upper limbs  were selected for rest tremor.2.22; voxel size = 1 × 1 × 1 mm3; a total of 196 layers. Enhanced T2 star‐weighted angiography sequence was used for reconstructing QSM, and the parameters were as follows: FOV = 240 × 240 mm2, TR = 33.7 ms, TE1/space/TE8 = 4.556 ms/3.648 ms/30.092 ms, matrix = 416 × 384, layer thickness = 2 mm, a total of 68 layers. DTI was performed to conduct tractography and scanned by a spin echo‐echo planar imaging sequence: 30 gradient directions; B value =0, 1000 s/m2; TR = 8000 ms; TE = 80 ms; flip angle = 90°; FOV = 256 × 256; matrix = 128 × 128; slice thickness = 2 mm; a total of 67 layers. At the same time, the opposite phase DTI data were collected to correct the susceptibility distortion.A 3.0T MRI scanner  with an eight‐channel head coil was used to scan all of the participants. Earplugs and foam pads were utilized to decrease noise and head movements for each participant. Fast spoiled gradient recalled sequence was used to capture structural T1 images: repetition time (TR) = 8.1 ms; echo time (TE) = 3.0 ms; inversion time = 450 ms; flip angle = 11°; field of view (FOV) = 256 × 256 mm2.3The Susceptibility Tensor Imaging (STI) Suite V3.0 software (Duke University) was used to process phase images on a computer cluster,www.itksnap.org) by a radiologist who was blinded to the all clinical data ,a Figure . Then, ta Figure .2.4https://fsl.fmrib.ox.ac.uk/fsl/fslwiki) was used to process DTI images. The following steps were included in the preprocessing procedures: (1) brain extraction with the “BET” tool; (2) the B0‐inhomogeneity distortion correction by using two opposite phase‐encoded images and the “topup” tool; (3) the eddy‐current‐induced handling motion and distortion correction by the “eddy” tool; and (4) fitting of DTI metrics  with “DTIFIT” tool.The FMRIB Software Library (FSL) v6.0 package  in native T1‐weighted images Figure .29 TheThe DRTT was calculated using probabilistic fiber tractography and FSL's diffusion toolkit “Fdt”,To visualize the spatial locations of two types of fiber bundles, all tracts of interest were normalized into the b0 template space using linear interpolation after native thresholding, and the group specificity map of each group was obtained by adding the fiber bundle probability values of all subjects in the same group. Then, we used the MNI space of the ICBM‐152 brain template to observe the spatial relationship between two types of DRTT tracts and the thalamic ventral intermediate nucleus (VIM)2.5All the statistical analyses were conducted by IBM SPSS Statistics v.25.0. Normal distribution of data was checked using the Kolmogorov–Smirnov test. To ensure normally distributed data, DTI metrics  were logarithmic transformed before statistical analysis.t‐tests were used to assess differences in the UPDRS‐III scores, rest tremor scores, action tremor scores, AR scores, PIGD scores, and disease duration between PD subgroups and between PD and ET. In addition, an independent sample t‐test was used to compare the difference in Hoehn–Yahr stage between two PD subgroups.The fundamental demographic differences in the three groups  were compared, including Pearson chi‐squared analysis for sex and analysis of variance for age, education, MMSE scores, and total intracranial volume (TIV). Independent samples p < 0.05 was regarded as statistically significant. Moreover, Bonferroni correction was applied in multiple comparisons to reduce type I error. Thus, p < 0.0083 (0.05/6) was judged as statistically significant for regional magnetic susceptibility, p < 0.00625 (0.05/8) for the nucleus volume and p < 0.0125 (0.05/4) for DTI metrics.For image analysis, because a direct comparison of ET with PD involves many confounders , the following design would help to better analyze the changes and effects of DRT pathway under different tremors. We used general linear models (GLM) to compare the differences in image parameters of DRT pathway between different groups: (1) NC vs ET, with sex and age as covariates, (2) PD‐RT vs PD‐WT, with sex and age as covariates, and (3) NC vs PD, with sex, age, education, and MMSE scores as covariates. In addition, TIV was added as a covariate when comparing nucleus volume between groups. Finally, partial correlation analysis was used to investigate the relationships among clinical behaviors, DTI, and QSM parameters showing significant intergroup differences. Two‐tailed 33.1p = 0.22, NC vs PD: p = 0.37, ET vs PD: p = 0.65, PD‐RT vs PD‐WT: p = 0.96) and TIV  was found among NC, ET, and PD patients. The NC and ET groups had more females , higher educational , and MMSE scores  than the PD group. Considering that these intergroup differences in demographics and clinical symptoms may influence the results, age, and gender were included as covariates in the subsequent analyses of image parameters. In addition, education level and MMSE score were used as covariates in the comparison between the NC and PD groups.We selected 40 ET patients, 57 PD patients , and 41 NC from the cohort collected by our team from August 2014 to November 2020. As shown in Table p < 0.01) and higher action tremor (p < 0.01) than PD group. Between PD‐RT and PD‐WT patients, there was a statistical difference in UPDRS‐III scores (p = 0.03), while there was no significant difference in the action tremor scores (p = 0.54), AR scores (p = 0.60), PIGD scores (p = 0.31), Hoehn–Yahr stage (p = 1.00), and disease duration (p = 0.27).The ET patients had longer disease duration . The bilateral SN magnetic susceptibility in the PD group was significantly higher than that in the NC group . No other intergroup difference in regional magnetic susceptibility was observed among groups . No other intergroup difference in nucleus volume was observed among groups , while no difference in any other diffusion metrics. No difference in any other diffusion metrics was found between PD and NC or among PD subgroups   and TETRAS scores in right upper limbs  were significantly associated with decreasing the log MD in L‐nd‐DRTT, while TETRAS scores in right upper limbs  were significantly negative relationships with the log RD  in ET, the iron content in DN was significantly higher than in NC; (2) the nd‐DRTT and d‐DRTT overlap a lot in the TH, mainly on VIM, but nd‐DRTT is more posterior and medial to d‐DRTT; and (3) the MD and RD of the L‐nd‐DRTT in ET were significantly lower than that in NC, and had a negative relationship with tremor severity.As a primary beginning point of the DRT pathway, bilateral DN in ET patients had significantly increased iron concentration when compared to NC. According to a growing body of researches, the overactivation of DN is closely related to the synthesis of excitatory neurotransmitters such as glycine and glutamate,ET patients had significantly lower MD and RD in the L‐nd‐DRTT. In the adult brain, nerve fibers still have plasticity, which may be achieved through changes in axon diameter, axon density, and myelin sheath number.Moreover, the nd‐DRTT and d‐DRTT were found to be overlapped greatly in the TH, particularly on VIM. For medication‐resistant patients, deep brain stimulation and MRI‐guided focused ultrasound targeting the VIM have been shown to be effective in controlling tremor.For the downstream of the DRT pathway, there is no significance in the volume of the bilateral TH and RN, the same as the iron content in RN. This result may be related to the mild severity of tremor in the ET patients. Both TH and RN belong to the downstream of DRT pathway, and their damage may occur later.In summary, we mainly found changes in the two main components of DRT pathway in ET patients: (1) increased iron deposition of bilateral DN; (2) decreased MD and RD of L‐nd‐DRTT. Specifically, iron deposition in DN may be related to the overactivation of DN, while the decrease in MD and RD in nd‐DRTT may be related to fiber remodeling, both of which represent the possibility of overactivation of DRT pathway. In addition, a potentially interesting phenomenon in ET patients was observed, that was the iron content of DN was positively correlated with RD of nd‐DRTT. This is different from the excessive iron deposition in DN and decreased MD and RD in nd‐DRTT found in ET patients, which may mean that the changes in iron and fiber bundles may vary from disease stages that means when iron deposition reaches a certain extent in the future, it will have a negative impact on nerve fiber bundles.However, when comparing PD with NC, significantly increased iron content and decrease volume were only found in bilateral SN, which is consistent with the fact that iron accumulation in the SN characterizes PD.There are still some limitations in our study: First, the diagnostic criteria for ET depend on the Movement Disorders Society Statement,In summary, we systematically explored each component of the DRT pathway and revealed DN iron deposition and nd‐DRTT remodeling in action tremor, which was indicating the hypothesis of pathological overactivation of action tremor. In addition, no changes in the DRT pathway were found in rest tremor, suggesting that changes in the DRT pathway may be specific for action tremor.Xiaojie Duanmu contributed to the conception, organization, and implementation of the research project, the design and implementation of the statistical analysis, and writing of the first draft of the manuscript. Jiaqi Wen contributed to the conception, organization, and implementation of the research project, the design of the statistical analysis, and writing of the first draft of the manuscript. Sijia Tan contributed to the conception and organization of the research project, the design and review and comment of the statistical analysis, and the review and comment of the manuscript. Tao Guo and Cheng Zhou contributed to the conception, organization of the research project, the review and comment of the statistical analysis, and the review and comment of the manuscript. Haoting Wu, Jingjing Wu, Zhengye Cao, Xiaocao Liu, Jingwen Chen, Chenqing Wu, Jianmei Qin, and Luyan Gu contributed to the conception, organization of the research project, the implementation of the statistical analysis, and review and comment of the manuscript. Yaping Yan, Baorong Zhang, and Minming Zhang contributed to the review and comment of the research project and review and comment of the manuscript. Xiaojun Guan and Xiaojun Xu contributed to the conception and organization of the research project, design and review and comment of the statistical analysis, and writing of the first draft and review and comment of the manuscript.This work was supported by the Natural Science Foundation of Zhejiang Province (Grant nos. LY22H180002 and LQ21H180008), the National Natural Science Foundation of China , and the 13th Five‐year Plan for National Key Research and Development Program of China (Grant no. 2016YFC1306600).The authors declare no conflicts of interest.All patients signed an informed consent approved by the Medical Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine.Data S1.Click here for additional data file.


PRPS1. This enzyme generates phospho‐ribosyl‐pyrophosphate (PRPP), which is utilized in the synthesis of purines, nicotinamide adenine dinucleotide (NAD), and NAD phosphate (NADP), among other metabolic pathways. Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age. Supplementation of the purine and NAD pathways outside of PRPP‐dependent reactions is a logical approach and has been reported in a handful of patients, two with S‐adenosylmethionine (SAMe) and one with SAMe and nicotinamide riboside (NR). We present the clinical course of a fourth Arts syndrome patient who was started on therapy and review previously reported patients. All patients had stability or improvement of symptoms, suggesting that SAMe and NR can be a treatment option in Arts syndrome, though further studies are warranted.Phospho‐ribosyl‐pyrophosphate synthetase 1 (PRPS1) deficiency is secondary to loss of function variants in  Arts syndrome patients appear to have clinical improvement with S‐adenosylmethionine and nicotinamide riboside; however, larger studies are needed.1PRPS1 (OMIM *311850) is located at Xq22.3 and encodes for phospho‐ribosyl‐pyrophosphate synthetase 1 (PRPS1). Phospho‐ribosyl‐pyrophosphate (PRPP) is utilized in the synthesis of purines, pyrimidines, nicotinamide adenine dinucleotide (NAD), and NAD phosphate (NADP), as well as amino acids histidine and tryptophan.PRPS1 deficiency, also known as Arts syndrome (OMIM #301835), is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections. Infections often precipitate worsening of symptoms, and many individuals pass away in early childhood.PRPS1 is not well characterized. X‐linked hearing loss accounts for <1%–2% of nonsyndromic hearing loss overall and PRPS1 variants were not identified in large cohorts of patients with nonsyndromic hearing loss.PRPS1 variants range from asymptomatic to varying degrees of isolated hearing loss to a more severe CMTX5 or Arts syndrome phenotype, with significant phenotypic variability.PRPS1 variants associated with PRPS1 superactivity (OMIM #300661). It has been hypothesized that the effect of PRPS1 variants on the local structure, ATP binding site, allosteric sites, and interface areas can be associated with certain phenotypes; however, this is not well delineated.Given the importance of PRPP in the synthesis of purines and NAD(P), supplementation of these pathways is a logical approach for these patients. S‐adenosylmethionine (SAMe) serves as source of purine precursors that is PRPP‐independent Figure . Similar2PRPS1 c.383A>T  (NM_002764.4). This specific variant met ACMG criteria PM2, PP3, PP2, PP1, and PP5 with no population frequency in gnomAD, deleterious in silico predictions at a highly conserved amino acid, missense variant in a gene with low rate of benign missense variation , co‐segregation in affected family members, and likely pathologic classification in Clinvar and in Mercati et al.The patient is the first son of nonconsanguineous white parents. He was born at 36 weeks to a 30‐year‐old G4P3 mother whose pregnancy was complicated by intrauterine growth restriction. His birth weight was 1.89 kg (WHO 0.1st percentile), birth length was 46 cm (WHO 1.4th percentile), and birth head circumference was 31 cm (WHO 0.3rd percentile). He did not pass his newborn hearing screening and was noted to have congenital nystagmus and hypotonia. He was diagnosed with severe congenital bilateral sensorineural hearing loss by auditory brainstem response at 2 months of age and subsequently received hearing aids. An electroretinogram showed retinal dystrophy. Subsequent genetic testing revealed a likely pathogenic variant in After discussion with family, he was started on 200 mg daily (20 mg/kg/day) of SAMe at 19 months, which was increased to 400 mg daily (approximately 40 mg/kg/day) at 20 months. At 20 months, he was also started on 300 mg daily (approximately 30 mg/kg/day) of NR. Medication doses were based on prior dosing and the nearest available capsule size. Parents reported subjective improvement in strength and endurance with therapy. Over the next few months, he made significant developmental gains, including walking with a walker at 21 months. He had done well with occasional upper respiratory tract infections without regression in skills, worsening hypotonia, or increased respiratory needs.At 24 months of age, he had significant regression after cardiac arrest secondary to respiratory failure from rhinovirus/enterovirus. Full immunologic evaluation—including lymphocyte subpopulations, T and B cell subset distributions, and immunoglobulins—was normal. He had appropriate vaccine titers for vaccines received, as he was under‐vaccinated. Head CT did not show significant changes; however, there was artifact present from cochlear implants. Brain MRI was unable to be obtained due to incompatibility with cochlear implants. At discharge 3 weeks later, he had lost head control, was not able to sit unsupported, roll over, or feed by mouth, prompting G‐tube placement. He was discharged with cough assist and vest to assist with secretion clearance, but did not require other respiratory support. Over the next couple of months, he regained many milestones and acquired additional milestones. At 26 months, he was sitting independently, pulling to stand, crawling, speaking (one to two words), and has resumed eating by mouth. He has had another upper respiratory tract infection without any clinical decline. Uric acid and purine metabolites remained similar while on SAMe and NR. Methionine remained in the normal range.PRPS1 c.383A>T variant. Other female family members, including a maternal aunt with hearing loss, are undergoing cascade genetic testing.The patient's mother, who had childhood onset hearing loss, was found to be a carrier for the 3n = 2) or SAMe and NR (n = 1). Their clinical data is summarized with our case in Table To date, three other Arts syndrome patients have been previously treated with SAMe  and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. This article does not contain any studies with animal subjects performed by any of the authors.


The vertical and horizontal broken lines indicate the pre‐revised criteria, whereas the vertical and horizontal solid lines indicate the 2022 European Society of Cardiology/European Respiratory Society criteria. Portopulmonary hypertension (PoPH) is a subtype of pulmonary arterial hypertension (PAH), classified as group 1 pulmonary hypertension (PH).Accordingly, the 2022 ESC/ERS guidelines will increase the number of PoPH cases. However, real‐world data on the extent to which patients with PoPH are diagnosed after the publication of the 2022 ESC/ERS guidelines are still limited. Previously, we retrospectively studied 186 patients with liver cirrhosis who underwent hepatic venous catheterization and right heart catheterization simultaneously for diagnosing portal hypertension and PoPH. Among these patients, two (1.1%) were diagnosed with PoPH according to the pre‐revised criteria.In this post hoc study, we aimed to investigate how the 2022 ESC/ERS guidelines modified the diagnosis of PoPH in these patients with liver cirrhosis complicated by portal hypertension.Among 338 patients with liver cirrhosis who underwent hepatic vein catheterization for a definitive diagnosis of portal hypertension at the Nippon Medical School, 186 patients were diagnosed with portal hypertension and simultaneously underwent right heart catheterization, as previously reported.Conventionally, PoPH was defined as the presence of portal hypertension, mPAP ≥ 25 mmHg, PVR > 3 WU, and PAWP ≤ 15 mmHg according to the pre‐revised diagnostic criteria. Meanwhile, according to the newly proposed definition, PoPH is the presence of portal hypertension, mPAP > 20 mmHg, PVR > 2 WU, and PAWP ≤ 15 mmHg based on the 2022 ESC/ERS guidelines.This study was conducted in accordance with the ethical guidelines established in the 2013 Helsinki Declaration, and was approved by the ethics committee of the Nippon Medical School . Patients were given the option to abstain from participating in this retrospective study.P‐value of <0.05.Continuous variables are presented as medians and ranges. Categorical variables are presented as numbers. Spearman's rank correlation coefficient was used to evaluate the association between mPAP and PVR. All statistical analyses were performed using SPSS version 17.0 software . The level of significance was set at a n = 61), chronic hepatitis B (n = 11), chronic hepatitis C (n = 91), autoimmune hepatitis (n = 2), primary biliary cholangitis (n = 4), non‐alcoholic steatohepatitis (n = 7), and others (n = 10). Child–Pugh classes A, B, and C accounted for 53, 92, and 41 patients, respectively. The median mPAP, PVR, PAWP, and CO were 13 (range 7–41) mmHg, 0.8 (range 0.1–4.5) WU, 8 (range 3–15) mmHg, and 6.7 (range 2.8–14.7) L/min, respectively.The patient population comprised 138 males and 48 females, with a median age of 59 (range 35–80) years, as previously described.Two 1.1%) out of the 186 patients had conventional PoPH, as reported previously..1% out oP = 7.44 × 10−5, r = 0.286). Echocardiography is recommended as the first noninvasive assessment approach for patients with portal hypertension or portosystemic shunt with suspected PH.This post hoc study assessed the clinical implications of the 2022 ESC/ERS guidelines of PAH for patients with liver cirrhosis complicated by portal hypertension. These guidelines increased PoPH prevalence from 1.1 to 2.2% in this patient cohort, suggesting that such guidelines may facilitate earlier identification of PoPH. Of note, no patients met the criterion of mPAP >20 mmHg alone or PVR >2 WU alone. As shown in Figure The prevalence of PoPH in patients with liver cirrhosis or portal hypertension is 1–6%.A strong point of this post hoc study is that it used data that included patients who had undergone hepatic venous pressure catheterization and right heart catheterization simultaneously. To our knowledge, there is no such (relatively) large cohort in Japan. However, this post hoc study lacks data on the effect of treatment for PoPH and prognosis of patients with and without conventional and newly diagnosed PoPH. In fact, the two patients diagnosed with PoPH by the new criteria died early because of refractory ascites. In addition, several background factors such as TRPG and BNP of the newly diagnosed patients were difficult to obtain because they were quite early patients. Future studies are required to address and clarify these issues along with the publication of the 2022 ESC/ERS criteria.The 2022 ESC/ERS guidelines identified patients with newly proposed PoPH in addition to those with conventional PoPH, thereby increasing the number of patients diagnosed with PoPH from 1.1 to 2.2% in this cohort. Further research is needed to elucidate how the 2022 ESC/ERS guidelines modify the clinical features and prognosis of patients with PoPH.


There is growing evidence that CEOs who have the ‘dark triad’ of personality traits  detrimentally influence firm performance. However, there is still much we do not know. The present study suggests that the CEO dark triad might directly influence typical performance indicators in different ways: positively affecting external performance indicators , but negatively affecting internal performance indicators . We argue that the CEO dark triad can be interpreted differently by those external to the firm versus internally, where managers are much closer to the CEO’s dark personality. Our model includes managerial capital as a mediator and competitive rivalry as a moderator, and ultimately tests a moderated mediation model. Using data from 840 New Zealand firms, we find that the dark triad links to outcomes, as expected. While the CEO dark triad is negatively related to managerial capital, managerial capital does positively predict both performance indicators, and partially mediates the CEO dark triad effect. Overall, moderating effects highlight that the CEO dark triad is less detrimental in fiercely competitive business environments, acting as a consistent boundary condition across models. As competitive rivalry increases, the indirect effect of the CEO dark triad on performance decreases. We discuss the implications for understanding the role that the CEO dark triad can play in firms. However, while the meta-analysis by Narcissism relates to internal insecurities and self-grandiose displays , such asInterestingly, research shows that employees with higher levels of dark triad factors are more likely to become leaders . CriticaOverall, the present study makes three contributions. First, using the logic of In their study, Despite growing attention to components of the dark triad such as narcissism e.g., , we undeRecent studies on firm performance have included leader dominance and self-esteem as positive influences , while Kvia the CEO. The authors also argued that researchers need to explore why and where dark traits might be conducive to good firm outcomes, suggesting that narcissists have a higher need for external approval, which might drive creativity. This is due to the importance of creativity  breakthrough sales and (b) organizational performance.Finally, we also expect managerial capital to mediate the effects of CEO personality, aligning with recent arguments . Thus, tHypothesis 5: Managerial capital will mediate the influence of the CEO’s dark triad on organizational performance.While the dark triad literature calls for mediation testing, it has also identified moderators as a key aspect that require more attention e.g., . For exavia managerial capital as the mediator) will be dependent on the moderator . Here, we expect that the indirect effect of the CEO dark triad will become weaker as competitive pressures rise, with the influence of managerial capital becoming more important  breakthrough sales and (b) organizational performance.Hypothesis 7: Competitive rivalry will interact with the CEO’s dark triad in terms of (a) managerial capital, (b) breakthrough sales, and (c) organizational performance, leading to stronger beneficial effects and weaker detrimental effects.Hypothesis 8: The indirect relationship between the CEO dark triad and (a) breakthrough sales and (b) organizational performance, via managerial capital, will be moderated by competitive rivalry. The indirect effects become weaker as rivalry increases (moderated mediation).via a Qualtrics survey panel of New Zealand firms. An initial screening question confirmed that respondents were in a senior management role  and were adequately able to reflect on their firm’s activities. CEOs were removed from the study. Researchers can copy this methodology by purchasing firm data through a similar panel, seeking a broad range of manager respondents  across a representative sample of firms within their country. Qualtrics ensures quality respondents (removing those who answer too fast or too slow and single response only), and this methodological approach has yielded positive samples , and the number of leaders contacted was increased until the target quota was achieved (here n = 840 respondents). Then, data collection was stopped. All participants answered all questions and thus were included in the study. They represent 840 senior managers from unique firms.A total of 840 participants were recruited early in 2020 (pre-COVID-19 events) es e.g., . OverallA meta-analytic comparison found that such panel data did not significantly differ from conventional data . While wRespondents had an average tenure in their current job of 7.79 years (SD = 5.7). Firms had an average age of 34.2 years (SD = 31.1) and were well spread by size: 24.4% were micro-sized (up to 10 employees), 25.1% were small-sized (11–50 employees), 26.0% were medium-sized (51–250 employees), and 24.5% were large-sized (251 or more employees). The average level of workplace education was similarly well spread: 24.3% had high school qualifications, 23.8% had technical college qualifications, 39.3% had bachelor’s degrees, and 12.6% had postgraduate qualifications. Finally, respondents came from a large number of different industries, with the largest being manufacturing (10.2%), retail (9.6%), education and training (9.0%), and professional services (8.9%). Our focus was on trying to gain generalizability of effects; thus, we had a wide industry focus.χ2(df) = 378.6(53), CFI = 0.97, RMSEA = 0.08, and SRMR = 0.03. The combined construct had excellent reliability (α = 0.97).The CEO dark triad was measured using the ‘dirty dozen’: a 12-item short measure by α = 0.77).Organizational performance was measured using four items from Breakthrough sales were used as an indicator of innovation performance following α = 0.83).Managerial capital was measured using the 3 items in We controlled for firm age (in years) and firm size 1 = micro-sized (up to 10 employees), 2 = small-sized (11–50 employees), 3 = medium-sized (51–250 employees), and 4 = large-sized (251 or more employees). We expect older firms to be more established and larger-sized firms to have greater resources that might shape performance e.g., . We alsoWe confirmed the distinct nature of the various study constructs using CFA in SEM with AMOS version 26, following standard thresholds . We testχ2(df) = 711.4(183), CFI = 0.96, RMSEA = 0.06, and SRMR = 0.04. Alternative measurement models resulted in a poorer fit  compared with the hypothesized model . Confidence intervals (CI) are reported as lower limits (LL) and upper limits (UL) at the 95% level. We explored the data for outliers and five were identified for firm size (being the largest) and two for age. The latter group of two firms was also in the first group. We tested models excluding and including these potential outliers; the effects remained the same; therefore, the entire sample was ultimately retained. Overall, data were normally distributed.Hypotheses were tested in SPSS (version 25) using the PROCESS 3.4 program . We usedDescriptive statistics for the study variables are shown in r = −0.21, p < 0.01), competitive rivalry , organizational performance , and breakthrough sales . Managerial capital is significantly correlated with competitive rivalry , organizational performance , and breakthrough sales . Competitive rivalry is significantly correlated with organizational performance  and breakthrough sales , and the two performance indicators are only modestly correlated . Importantly, this analysis confirms that the CEO dark triad is significantly correlated with both firm performance indicators, in opposite directions.The results of the direct and mediation analyses of firm performance indicators are shown in β = −0.18(0.03), p < 0.001 ), organizational performance (β = −0.14(0.02), p < 0.001 ), and breakthrough sales (β = 6.2(0.9), p < 0.001 ), supporting Hypotheses 1–3. Managerial capital is significantly related to organizational performance (β = 0.45(0.02), p < 0.001 ) and breakthrough sales (β = 5.3(1.1), p < 0.001 ), supporting Hypotheses 4a and 4b. The inclusion of managerial capital in the models partially mediates the effect of the CEO dark triad on organizational performance, with the direct effect decreasing (β = −0.07(0.02), p < 0.001 , although the indirect effect remains significant. In terms of breakthrough sales, there is a slight increase (not decrease) in the direct effect of the CEO dark triad (β = 7.0(0.9), p < 0.001 ). This provides support for the mediation argument regarding organizational performance (Hypothesis 5) and confirms that there is no mediation effect on breakthrough sales.The results show that the CEO dark triad is significantly related to managerial capital (β = 0.34(0.04), p < 0.001 ), organizational performance (β = 0.10(0.03), p < 0.001 ), and breakthrough sales (β = 8.4(1.4), p < 0.001 ), supporting Hypotheses 6a–6c.Regarding the direct effect of competitive rivalry, this was significantly related to managerial capital , p = 0.005 ) and organizational performance (β = 0.06(0.02), p = 0.002 , but not breakthrough sales (β = 1.4(1.1), p = 0.201 ). This supports Hypotheses 7a and 7c. Finally, regarding the moderated mediation (Hypotheses 8), a significant indication of moderated mediation was found in terms of competitive rivalry on the indirect effect of the CEO dark triad on breakthrough sales, with managerial capital (index = 0.51(0.24), p = 0.016, LLCI = 0.06, ULCI = 1.0) and organizational performance (index = 0.04(0.02), p = 0.008, LLCI = 0.01, ULCI = 0.08) mediating. This supports both Hypotheses 8a and 8b. We graphed the interaction to illustrate the effects, and these graphs are shown in Significant interactions were found between the CEO dark triad and competitive rivalry in terms of managerial capital , p < 0.001; LLCI = −2.1; ULCI = −0.63), and, at average competitive rivalry (mean), the indirect effect is significant and negative but weaker (β = −0.97(0.29), p < 0.001; LLCI = −1.6; ULCI = −0.47). Finally, when competitive rivalry is fierce (+2SD), the indirect effect of the CEO dark triad is still significant and negative but drops in strength again (β = −0.63(0.25), p = 0.006; LLCI = −1.2; ULCI = −0.23). While the indirect effect is significant across the full 95% confidence intervals, the indirect effect of the CEO dark triad on breakthrough sales decreases as firms report stronger competitive rivalry, providing support for Hypothesis 8a.β = −0.11(0.02), p < 0.001; LLCI = −0.15; ULCI = −0.07), and at average competitive rivalry (mean), the indirect effect is significant and negative but weaker (β = −0.08(0.01), p < 0.001; LLCI = −0.11; ULCI = −0.06). Finally, when competitive rivalry is fierce (+2SD), the indirect effect of the CEO dark triad is still significant and negative, but weaker again (β = −0.05(0.02), p < 0.001; LLCI = −0.09; ULCI = −0.03). While the indirect effect is significant across the full 95% confidence intervals, the indirect effect of the CEO dark triad on organizational performance decreases as firms report stronger competitive rivalry, again supporting Hypothesis 8b.Regarding organizational performance, we find that in weak competitive rivalry settings (−2SD), the indirect effect of the CEO dark triad on organizational performance vis-à-vis managerial capital is significant and negative  and professional services (positive). In terms of breakthrough sales, firm size is significantly and negatively related, while firm age and manufacturing are significantly and positively related. Overall, the models are all significant (p < 0.001) and account for robust but modest levels of variance for managerial capital (15%) and breakthrough sales (22%), but large amounts of variance for organization performance (49%).The study of the effects of CEO personality on firm performance is still in its infancy, and scholars have urged for more testing. Further, researchers have also called for the incorporation of mediation and moderation effects e.g.,  and to eOur other direct effect hypothesis followed arguments made by Beyond the CEO dark triad, we explored managerial capital as a mediator, because theoretical arguments e.g.,  and empiInterestingly, managerial capital did partially mediate the direct effect of the CEO dark triad on organizational performance, although the direct effect of the CEO dark triad was still significant. This suggests that not only does managerial capital positively shape organizational performance but CEOs with strong dark personalities are still able to shape the nature of their firm . While managerial capital positively influenced breakthrough sales, as expected, there was no mediating effect on the CEO dark triad’s positive influence on breakthrough sales. This highlights a unique finding. The CEO dark triad can positively influence breakthrough sales and this effect is not impacted by the strength of managerial capabilities. This reinforces the calls made by These findings have important implications for organizational ethics, which often argue that the CEO’s dark triad can encourage unethical behaviors , 2022. TTwo-way interactions show that when firms report CEOs with high levels of the dark triad, they can maintain high levels of managerial capital and organizational performance when they operate in fiercely competitive environments. This supports our argument that firms in such environments face strong pressure to react, to be decisive, and to overcome external pressures. However, firms operating in low competitive rivalry environments do provide greater opportunity for the CEO’s offensive personality to be viewed as such, which exerts adverse internal reputational effects on the firm. We also suggested that the moderated mediation effect might counter any potential “benefit’ of a CEO dark triad, with the indirect effect weakening as competitive rivalry increased, and this was supported. Given the direct and positive effect of managerial capital—which aligns with theories on TMT factors that can disrupt the leader’s dark personality —we expecWe also highlight an important finding from the moderated mediation models. Despite the CEO dark triad being directly related to both performance outcomes, in opposite directions, we find that the indirect effect was negative and weakened as competitive rivalry strengthened. Here, the indirect effect of the CEO dark triad on breakthrough sales becomes negative, opposite to the direct effects. This reinforces the arguments made by The implications of the present study are that firm performance might be positively influenced by the CEO dark triad, at in terms of toward breakthrough sales. Despite strong evidence that the dark triad is detrimental to employee performance , the preLikely, boards of directors might already be aware of these issues with such CEOs, even if they are not specifically aware of the terminology. In the New Zealand context, where employee protections are strong, it might not be as simple as “firing” the CEO. However, managing an exit might be a real option if the CEO is creating major disruptions within a firm. While encouraging CEOs high on these dimensions to “move along” might be useful, we acknowledge that their confidence and persona might make them easily “hireable” for new CEO roles. In a similar fashion, this does not also stop a firm from replacing one dark triad CEO with another. Our findings suggest that tapping into TMTs to gain insights into any new CEO appointments might be especially useful.how effects are materialized would also be useful. Similarly, understanding how those immediately below the CEO  cope and manage CEOs with high levels of the dark triad would be insightful. Future research might explore other mediators around the TMT and also test the multi-level theoretical model of Research implications include more exploration of the CEO dark triad to better understand the effects on firm performance and indeed, whether our dual-edge performance effects hold. Qualitative research on how firms manage and/or expedite the exit of CEOs with high levels of the dark triad would be valuable. Indeed, mixed methods might prove especially insightful for understanding CEO dark triad effects. Following this up with interviews to ascertain post hoc testing. We undertook the procedure described by A limitation of the present study is that the data is single-sourced. However, we followed suggestions made by The present study explored the potential of the CEO dark triad positively influencing firm performance and provided a more nuanced understanding of relationships by exploring mediator, moderator, and moderated mediation. In doing so, we have uncovered evidence that CEOs with high levels of the dark triad can benefit a firm on one performance indicator . However, the evidence also suggests that this does not stop them from detrimentally impacting managerial capital and organizational performance, indicating that such leadership comes at a cost. We also found that the environmental context plays a largely beneficial role, bringing out the best in dark triad CEOs and also acting as a boundary condition, minimizing the indirect effect of the CEO’s dark triad as competitive rivalry strengthens. As a result of this study, we have a stronger understanding of how this dark personality impacts the way firms operate.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Auckland University of Technology Ethics Committee . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JH contributed to conceptualization, data collection and analysis, and writing. The first draft of the manuscript was written by JH and KJ. Both authors commented on previous versions of the manuscript and read and approved the final manuscript.Kia kotahi mai - Te Ao Pūtaiao me Te Ao Hangarau].This study was funded by the New Zealand National Science Challenge: Science for Technological Innovation [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.


Increased preoperative red cell distribution width (RDW) is associated with poor prognosis in several cancers, but the relationships between preoperative RDW and changes in RDW (ΔRDW) and colorectal cancer (CRC) prognosis remain unclear. Our study aimed to demonstrate the prognostic significance of increased preoperative RDW and ΔRDW for CRC.In this retrospective analysis, we enrolled 833 patients who underwent CRC surgery between 2015 and 2019 at the Affiliated Hospital of Xuzhou Medical University, China. ΔRDW in our study was defined as RDW at 1 month after discharge minus preoperative RDW. According to receiver operating characteristic (ROC) curve analysis, we used cut‐off values of 13.5% for RDW, 0.9% for ΔRDW. The cumulative survival rate was determined using the Kaplan–Meier method, and significant differences were evaluated by the log‐rank test. Multivariable Cox regression model was applied to clarify the independent risk factors for overall survival (OS), which were used to construct a nomogram prediction model. The competing risk method was also applied, and we analyzed only patients with early‐stage disease (stage 0‐II) for sensitivity analysis.p < 0.05). These prognostic factors were used to establish and verify the OS nomogram. Poorer OS was linked to higher RDW  and ΔRDW  in all‐stage patients, and was only linked to higher RDW in early‐stage patients. In competing risk model, H‐RDW and H‐ΔRDW were confirmed to be independent risk factors for CSS in CRC patients.Multivariable Cox regression analysis demonstrated that age, RDW, ΔRDW, postoperative adjuvant chemotherapy, CEA, CA19‐9, ASA, TNM stage, and pathological type were independent factors for OS in CRC patients (all High preoperative RDW and ΔRDW are both risk factors for OS and CSS in CRC. This study used information from CRC patients in the Affiliated Hospital of Xuzhou Medical University, China. We found that patients with increased preoperative RDW and ΔRDW tended to have a worse prognosis. Preoperative RDW combined with ΔRDW, postoperative adjuvant chemotherapy, age, ASA, TNM stage, histological type, CEA, and CA19‐9 can be used to accurately predict the prognosis of CRC patients. The results remind us that we need to concentrate on patients with high RDW in future work.1Colorectal cancer (CRC) is the most common malignant tumor of the digestive tract and the fourth major cause of cancer‐related deaths globally, with 900,000 deaths annually.The red cell distribution width (RDW) is a metric used to describe the heterogeneity in the size of circulating red blood cells in a complete blood cell count. It is computed by dividing the mean red cell volume (MCV) by the standard deviation of the red cell volume (SD), and then multiplying that result by 100%. RDW was initially used to diagnose and differentiate anemia in combination with MCV.In recent years, RDW has been studied as a potential prognostic factor for CRC. However, the prognostic role of RDW remains unclear, as published studies have shown different results. Some reports have confirmed that high preoperative RDW is a strong predictor of the diagnosis and poor prognosis of CRC,In our study, we retrospectively enrolled 833 patients who underwent surgery for CRC between 2015 and 2019 at the Affiliated Hospital of Xuzhou Medical University. This study aimed to assess the prognostic roles of preoperative RDW and changes in RDW in CRC patients.22.1The Affiliated Hospital of Xuzhou Medical University's Research Ethics Committee  approved this single‐center retrospective cohort study on March 1 (XYFY2022‐KL038‐01). The study was documented in the Chinese Clinical Trial Registry (ChiCTR2200056323). Individual consent was waived because we retrospectively collected information of patients in our study.2.2All patients undergoing primary tumor removal surgery for CRC between 2015 and 2019 at the Affiliated Hospital of Xuzhou Medical University Hospital in China were recruited. The inclusion criteria were as follows: patients with colorectal cancer who have been pathologically confirmed, aged 18 years or older. Exclusion criteria were: patients who experienced a second operation for a recurrence of CRC cancer, patients complicated with other tumors, perioperative blood transfusion and transfusion history within 3 months, patients who lacked perioperative RDW value prior to the operation and other clinical data.2.3p < 0.05).First, the preoperative RDW cut‐off value was considered based on the receiver operating characteristic (ROC) curve with 5‐year OS as the outcome. The RDW cohort was divided into H‐RDW and L‐ RDW using RDW = 13.5% as the cut‐off value. , white blood cell (WBC) count, platelet count, serum albumin level, neutrophil count (NEUT), aspartate aminotransferase (AST), direct bilirubin, perioperative RDW, RDW at 1 month after discharge, serum CEA level, serum CA19‐9 level, ASA, the type of operation, TNM stage, histological type, histologic grade, tumor location, tumor size, and postoperative adjuvant chemotherapy. We also collected the information of comorbidities including hypertension, diabetes mellitus, coronary heart disease (CHD), chronic obstructive pulmonary disease (COPD), and history of stroke. The 8th Edition of the American Joint Committee on Cancer (AJCC) criteria were followed while reporting pathology specimens.2.5We used telephone interviews or electronic medical records to follow up the patient's survival until October 2022. The time of survival was calculated from the date of surgery to the most recent follow‐up or death.The primary outcome of the study was overall survival (OS). OS was defined from the moment the patient received surgery until death, regardless of the cause. The secondly outcome was cancer‐specific survival (CSS). CSS was defined as the time from surgery to cancer‐related death.2.6p < 0.05. The final variables screened by the above methods were used to construct models predicting OS. The model with the largest area under the curve (AUC) was selected for constructing the nomogram. The effectiveness of RDW for OS prediction was evaluated using a receiver operating characteristic (ROC) curve. The calibration curve and concordance index (C index) were also employed to evaluate the model's performance. A bootstrap approach was applied to decrease the overfit bias. Deaths from colorectal cancer and deaths from other causes were treated as competing events in our study. To explore the possible effect of competing events on the risk factors of CRC patients, we performed cause‐specific hazards model to investigate the CSS of patients.The Kolmogorov–Smirnov test was performed to determine if the continuous data followed a normal distribution. Normally distributed quantitative data are expressed as the mean ± standard deviation (SD), and nonnormally distributed data are represented by the median and interquartile range (IQR). Categorical data are displayed as numbers and percentages. The Reverse Kaplan–Meier method was used to determine the median follow‐up period. The cumulative overall survival rate of CRC patients was determined using the Kaplan–Meier method, and significant differences were evaluated using the log‐rank test. Univariable Cox regression, all‐subset regression, and lasso regression were used to screen the initial variables. Then, these initial variables were separately put into the multivariable Cox regression for final screening the prognostic factors of OS. We used the backward stepdown process and selected final variables with Sensitivity analysis was performed. In order to explore the role of preoperative RDW and changes in RDW in early‐stage CRC patients (stage 0‐II), we only analyzed the early‐stage CRC patients. Univariable and multivariable Cox regression analyses were performed to identify the risk factors of OS in early‐stage patients.All statistics were performed with R, version 4.2.1. In addition, the Survival, Survminer, Ggplot2, Rms, Plyr, Forestplot, and Table One packages in R were used for statistical analysis.33.1n = 3), complications with other tumors (n = 2), perioperative blood transfusion and transfusion history within 3 months (n = 63), and incomplete records of clinical data (n = 13) were excluded. During the study, 865 patients met the inclusion criteria and were enrolled. A total of 833 patients were eventually followed up, while a total of 32 patients were lost to follow‐up. The follow‐up period ranged from 0.8 to 90.9 months, with a median of 60.1 months . At the end of the follow‐up, 176 patients had passed away. The 1, 3, and 5‐year OS rates were 97.3%, 86%, and 77.5%, respectively. The CSS rates at 1 year, 3 years, and 5 years were 97.6%, 86.5%, and 78.3%, respectively. Table Patients with relapse , and the H‐ΔRDW group also had worse CSS (log‐rank p < 0.01). .The Kaplan–Meier analysis revealed that the patients with increased RDW had a lower OS than those with RDW <13.5% , and ΔRDW was also a prognostic value in CRC .These independent risk factors  were selected to establish an OS risk prediction model for CRC patients . Univariable Cox analysis showed that age, patients with diabetes mellitus, history of stroke, RDW, AST, CEA, CA19‐9, ΔRDW, ASA, the type of operation, TNM stage and neutrophil count were prognostic factors of CRC patients . In multivariable analysis, we found that patients with elevated preoperative RDW tended to have a worse survival rate  , and RDW was divided into H‐RDW and L‐ RDW using RDW = 13.5% as the cut‐off value  there was an association between increased preoperative RDW and OS and CSS in all‐stage CRC patients, which was consistent with the findings of previous studies.The mechanism of the association between elevated RDW and poor prognosis in CRC patients remains unclear. It is speculated that the following three mechanisms may be involved: (1) In the process of tumor development, cancer‐related inflammation plays a critical role.The current study has several limitations. First, this was a single‐center retrospective study with a biased population selection, so further prospective studies are needed to demonstrate the role of RDW and ΔRDW in CRC patients. Second, statistically speaking, RDW was an independent prognostic risk factor in all‐stage CRC patients, but HR of RDW was 1.52, which was not very large, indicating that this single factor did not seem to play a very significant role in theOS of the colorectal cancer. There's no denying that RDW combined with ΔRDW, postoperative adjuvant chemotherapy, age, ASA, TNM stage, histological type, CEA, and CA19‐9 can accurately predict the OS of CRC patients. However, in the sensitivity analysis of early‐stage patients, we found that the prognostic value of RDW in OS was more significant than that of all‐stage patients. It can be explained that the TNM stage plays an increasingly important role in the prognosis of patients with advanced cancer. In our sensitivity analysis, we may not have assessed enough population to explore the role of RDW in early‐stage patients. Third, RDW = 13.5% and ΔRDW = 0.9% were defined as the cut‐off values according to the ROC curves of 5‐year OS in this study, which were only applicable to our study population. Further multicenter large sample studies are needed to explore appropriate cut‐off values. In conclusion, we found that preoperative RDW (≥13.5%) and ΔRDW (≥0.9%) were independent predictors of OS and CSS in CRC patients. Future clinical work should pay attention to CRC patients with elevated RDW and adopt a scientific intervention strategy to improve the prognosis of CRC patients.Xian Lu: Conceptualization ; data curation ; formal analysis ; investigation ; methodology ; writing – original draft ; writing – review and editing . Xiaofan Huang: Conceptualization ; data curation ; formal analysis ; methodology ; writing – review and editing . Meng Xue: Conceptualization ; investigation ; methodology ; writing – review and editing . Zhenyu Zhong: Conceptualization ; methodology ; writing – review and editing . Ran Wang: Conceptualization ; methodology ; writing – review and editing . Wen Zhang: Conceptualization ; methodology ; writing – review and editing . Lili Wang: Conceptualization ; investigation ; methodology . Yuhan Qiao: Conceptualization ; investigation ; methodology . Fei Ling: Conceptualization ; investigation ; methodology . Qian Zhang: Conceptualization ; investigation ; methodology . Yueying Zhang: Conceptualization ; methodology ; writing – original draft ; writing – review and editing .This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.The authors declare that they have no conflicts of interest.Figure S1Click here for additional data file.Figure S2Click here for additional data file.Figure S3Click here for additional data file.


Nigella sativa, commonly known as the black seed, is a culinary spice therapeutic against many ailments. Common preparation practice of roasting or heating the seeds often deteriorates bioactive compounds, which can be remedied with superheated steam (SHS). With roasting temperatures of 150, 200, and 250°C and roasting times of 10, 15, and 20 min, convection and SHS roasting media were tested, and their effects on proximate analysis, antioxidant assays, and oil quality were evaluated. For proximate content, moisture significantly decreased from 9.08% in unroasted seeds to 4.18%–1.04% in roasted seeds, while fat increased to as high as 44.76% from 32.87% in unroasted seeds. Roasting only slightly increased ash content and had no significant impact on protein and carbohydrate content. SHS roasted black seeds had better DPPH  radical scavenging capacity (RSC) than convection roasted seeds. DPPH RSC decreased with elevated roasting time and temperature, conversely related to total phenolic content, which increased with increased roasting time and temperature. Oil of roasted seeds developed an increasingly intense brown color from an initial light, yellow, unroasted oil with better extraction efficiency in SHS roasting. For oil quality analysis, free fatty acid values were significantly lower in both roasted samples. Peroxide value was initially recorded at 84 in convection and 48 (meq O2/kg of oil) in SHS roasted samples. In contrast, p‐anisidine values were initially recorded at 28.36 in convection roasted samples compared to 23.73 in SHS roasted samples. Based on all quality analyses, SHS showed better potential in black seed quality preservation. With roasting temperatures of 150, 200, and 250°C and roasting times of 10, 15, and 20 min, convection and superheated steam (SHS) roasting media were tested, and their effects on proximate analysis, antioxidant assays, and oil quality were evaluated. SHS roasted black seeds had better 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) radical scavenging capacity (RSC) than convection roasted seeds. Based on all quality analyses, SHS showed better black seed quality preservation potential. Chloroform and phenolphthalein were purchased from R&M Chemicals.2.2Black seeds procured from local vendors were air‐tight sealed and stored at room temperature until roasting was carried out. Vendors verified that the seeds were of Indian origin. Seventy grams of seeds were roasted with convection and SHS using a SHARP Healsio AX‐1500V oven (Japan) at 150, 200, and 250°C for 10, 15, and 20 min at each temperature. Temperature and time parameters were modified from Liang et al.'s work , and Idr2.3Proximate analysis was carried out according to AOAC's official Method of Analysis AOAC, . Moistur2.4Extraction for antioxidant assays was done according to Brodowska et al. , with so2.5L*, a*, and b*, based on Zzaman et al.  at a significance level of 3Moisture, fat, protein, ash, and carbohydrate contents are necessary for the basic building blocks of food products and for reflecting changes that occur within different processes involved   to measure edible oil color , a* values indicate red‐to‐green color spectrum , and b* values represent the blue‐to‐yellow spectrum   and the Food and Agriculture Organization (FAO), there are guidelines for edible fats and oils, albeit unspecified (CXS 19‐1981), amended as late as 2019. These guidelines describe edible oil standards, including methods for expulsion and minimum acid and peroxide values. According to this standard, FFA values of virgin edible oils should not exceed 2.01 (% oleic acid), which means all samples in this work exceed the standard . Cold‐pressed black seed oils typically have lower peroxide values ranging from 4.1 to 9.7  from cold pressed oil at 65.4, with heatless mechanical pressed oil at approximately 25, and Soxhlet extracted oil at 70.8 and 20.7; all of which happened to fall within the range of peroxide value recorded in Table Peroxide value is an important analysis for measuring peroxides formed in oils during the early stages of lipid oxidation ; investigation ; resources ; software ; visualization ; writing – original draft . Nguyễn Hữu Tiến: Investigation ; methodology ; resources ; visualization ; writing – original draft . Toàn Nguyễn Song Đinh: Data curation ; investigation ; validation ; visualization ; writing – original draft . Hayati Samsudin: Conceptualization ; project administration ; supervision . Fazilah Ariffin: Conceptualization ; data curation ; funding acquisition ; methodology ; project administration ; supervision ; validation . Abdorreza Mohammadi Nafchi: Data curation ; formal analysis ; methodology ; project administration ; validation ; visualization ; writing – review and editing .This research was funded by RUI grant (1001.PTEKIND.8011042). The authors acknowledge School of Industrial Technology, Universiti Sains Malaysia, for staff, lab assistance, and facilities provided.The authors declare no conflict of interest.This study does not involve any human or animal testing.


Previously, few studies investigated level of adherence to option B+ lifelong antiretroviral therapy (ART) in Ethiopia. However, their findings were inconsistent. Therefore, this review aimed to determine the pooled magnitude of adherence to option B+ lifelong ART and its predictors among human immune virus (HIV)‐positive women in Ethiopia.I2 statistics were utilized to assess publication bias and heterogeneity among included studies respectively.A comprehensive web‐based search was conducted using PubMed, Cochrane Library, Science Direct, Google scholar, and African Journals Online databases to retrieve relevant articles. STATA 14 statistical software was used to carry out the meta‐analysis. We used the random effects model to account for the large heterogeneity across included studies. Egger's regression test in conjunction with funnel plot and I2 = 85.4%). Disclosure of sero‐status (OR 2.58 [95% CI: 1.55−4.3]), receiving counseling (OR 4.93 [95% CI: 3.21−7.57]), attending primary school and above (OR 2.45 [95% CI: 1.31−4.57]), partner support , good knowledge about prevention of mother‐to‐child transmission (PMTCT) (OR 4.22 [95% CI: 2.02−8.84]), taking less time to reach health facility (OR 1.64 [95% CI: 1.13−2.4]), and good relation with care provider (OR 3.24 [95% CI: 1.96−5.34]) were positively associated with adherence. Whereas, fear of stigma and discrimination (OR 0.12 [95% CI: 0.06−0.22]) and advanced disease stage (OR 0.59 [95% CI: 0.37−0.92]) were negatively associated.Twelve studies with a total of 2927 study participants were involved in this analysis. The pooled magnitude of adherence to option B+ lifelong ART was 80.72% (95% confidence interval [CI]: 77.05−84.39; The level of adherence to option B+ lifelong ART was suboptimal. Strengthened comprehensive counseling and client education on PMTCT, HIV status disclosure, and male partner involvement are important to eliminate mother to child transmission and control the pandemic. In Ethiopia, few studies reported the magnitude of adherence to option B+ PMTCT program. However, they present inconsistent findings and failed to summarize the national adherence level. Hence, this study was conducted to determine the magnitude of ART adherence and its predictors among HIV‐positive pregnant and lactating women on option B+ PMTCT program in Ethiopia.22.1This systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement.2.2A comprehensive web‐based literature search was conducted using PubMed, Cochrane Library, Science Direct, Google scholar, and African Journals Online databases to retrieve relevant articles. Besides, gray literature like Google and online University repositories  were scrutinized. Reference list of pertinent articles were also audited to identify additional studies. The search was conducted from June 1 to June 26, 2022. We utilized the following search string for searching in PubMed database; ((((((adherence[tw] OR compliance[tw])) OR (“Treatment Adherence and Compliance”[Mesh] OR “Medication Adherence”[Mesh] OR “Patient Compliance”[Mesh]))) AND (((Option B plus[tw]) OR )) AND ((women) OR (“Women”[Mesh] OR “Pregnant Women”[Mesh] OR “Postpartum Period”[Mesh]))) AND Ethiopia.2.3This review included all primary studies conducted in Ethiopia and fulfills the following criteria.Study area: studies conducted only in Ethiopia.Study design: all observational studies  that reported the magnitude and/or predictors of adherence to option B+ PMTCT during pregnancy, lactation, or both.Language: articles that were published in the English language between June 2013 and June 26, 2022, were considered.Population: HIV‐positive pregnant and/or lactating women who are on option B+ PMTCT.Exposure: predictors of adherence to option B+ PMTCT. These are characteristics that may increase or decrease women's adherence to option B+ PMTCT, such as age, residence, educational status, disclosure of HIV status, drug side effect, and so forth.Outcome: adherence to option B+ PMTCT.However, editorials, duplicate studies, abstracts without full text, studies that were conducted before the option B+ era, and studies that reported adherence on nonpregnant and/or nonlactating women were excluded from this study. Besides, qualitative studies without the outcome of interest were also excluded from this analysis.2.4The magnitude of adherence to option B+ PMTCT among HIV‐positive pregnant and lactating women was our primary outcome of interest. There are several methods to measure adherence; commonly it can be measured by the self‐report method, pill count method, or else a combination of these methods can also be employed.2.5After removing duplicates, studies were screened based on their title and abstracts. For articles found to be relevant by title and abstract, a full‐text review against the specified inclusion/exclusion criteria was conducted to identify potential articles to be included in this review. We utilized reference management software (Endnote version X7.2); to combine database search results, remove duplicate entries and manage the citation process.The Joanna Brigg's Institute (JBI) quality assessment checklist for prevalence studies was used to assess the quality of included studies.We used a standardized data‐extraction form which was developed considering the JBI guide for data extraction and synthesis.2.6I2 statistics in conjunction with p values were used to assess heterogeneity between studies, and it was considered as low, moderate, or high when I2 test statistics results were 25%, 50%, and 75% respectively.p value less than 0.05 was used to declare the presence of publication bias. Besides, sensitivity analysis was done to assess the influence of each study on the overall meta‐analysis estimate.Microsoft Excel spreadsheet was used to extract data from primary studies. Then, extracted data were exported to STATA version 14 for further statistical analysis. The 33.1A total of 1012 studies were identified through the combined literature search. Of which, 127 duplicates were removed and 865 studies were excluded after screening by title and abstracts. One study was excluded due to the inaccessibility of the full text. Finally, the full texts of 19 studies were assessed for eligibility, and 12 studies were found to be appropriate for consideration in the quantitative meta‐analysis . According to the sub‐group analysis by methods used to measure adherence, the magnitude of adherence among studies that used the self‐report method was 81.53% (95% CI: 77.22−85.84). Whereas that of studies that employed both self‐report and pill count methods was 78.66%  . This is further corroborated by the symmetrical funnel plot , women who received counseling (OR 4.93 [95% CI: 3.21−7.57]), women who attended primary school and above (OR 2.45 [95% CI: 1.31−4.57]), women who reside in urban areas (OR 2.28 [95% CI: 1.51−3.43]), women who receive support from their partner (OR 2.24 [95% CI: 1.11−4.52]), women who had good knowledge about PMTCT (OR 4.22 [95% CI: 2.02−8.84]), women who need less than 1 h to reach the health facility (OR 1.64 [95% CI: 1.13−2.4]) and women who had good relation with care provider  were more likely to adhere to option B+ PMTCT. On the other hand, women who had fear of stigma and discrimination (OR 0.12 [95% CI: 0.06−0.22]) and women with advanced disease stage (OR 0.59 [95% CI: 0.37−0.92]) were having higher risk of nonadherence to the regimen . This finding is lower than the WHOs' recommendation for optimal effectiveness of lifelong ART.Our meta‐analysis also identified determinants of adherence to option B+ PMTCT. Consequently, women who disclosed their sero‐status were 2.58 times more likely to adhere to the regimen as compared to women who did not disclose. This association is documented elsewhere,In line with previous studies, our analysis found that educational status was significantly associated with adherence to PMTCT.The odds of adherence were 2.24 times higher among women who received partner support as compared to those women who had not. This finding is congruent with findings of previous studies,This meta‐analysis also revealed that women who walked for less than 1 h to reach the health facility were 1.64 times more likely to adhere than women who walk for an hour or more. This could be attributed to the increased physical barrier and nontherapeutic cost associated with farther distances.This study has certain limitations. Firstly, studies published only in the English language were considered. Some variables were not included because of variation in categorization across primary studies. Furthermore, all included studies were cross‐sectional therefore temporal associations cannot be established.5This meta‐analysis found that the level of adherence to option B+ PMTCT among HIV‐positive women in Ethiopia is suboptimal. Hence measures targeting the identified risk factors, like strengthened comprehensive counseling and client education about the purposes of PMTCT and possible drug side effects, HIV status disclosure, and male partner involvement are compulsory to eliminate MTCT and control the pandemic; with great emphasis on rural residents and poorly accessed women. Besides, universal primary education among women would have a substantial contribution to amplify the effectiveness of lifelong ART.Habtamu Geremew: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; resources; software; validation; visualization; writing—original draft; writing—review and editing. Demeke Geremew: Data curation; formal analysis; investigation; methodology; project administration; resources; software; supervision; validation; visualization; writing—original draft; writing—review and editing. Samuel Abdisa: Data curation; investigation; methodology; project administration; resources; visualization; writing—review and editing. Anteneh Mengist Dessie: Data curation; investigation; methodology; project administration; resources; validation; writing—review and editing. Getachew Mullu Kassa: Investigation; methodology; project administration; supervision; validation; visualization; writing—review and editing. Nurilign Abebe Moges: Formal analysis; investigation; methodology; project administration; supervision; validation; visualization; writing—review and editing.The authors declare no conflict of interest.The lead author Habtamu Geremew affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned  have been explained.