The high co‐occurrence of somatic symptom disorder (SSD) in Parkinson's disease (PD) patients suggests overlapping pathophysiology. However, little is known about the neural correlates of SSD and their possible interactions with PD. Existing studies have shown that SSD is associated with reduced task‐evoked activity in the medial prefrontal cortex (mPFC), a central node of the default‐mode network (DMN). SSD is also associated with abnormal γ‐aminobutyric acid (GABA) content, a marker of local inhibitory tone and regional hypoactivity, in the same area when SSD co‐occurs with PD.To disentangle the individual and shared effects of SSD and PD on mPFC neurotransmission and connectivity patterns and help disclose the neural mechanisms of comorbidity in the PD population.The study cohort included 18 PD patients with SSD (PD + SSD), 18 PD patients, 13 SSD patients who did not exhibit neurologic disorders, and 17 healthy subjects (HC). Proton magnetic resonance (MR) spectroscopy evaluated GABA levels within a volume of interest centered on the mPFC. Resting‐state functional MR imaging investigated the region's functional connectivity patterns.Compared to HC or PD groups, the mPFC of SSD subjects exhibited higher GABA levels and connectivity. Higher mPFC connectivity involved DMN regions in SSD patients without PD and regions of the executive and attentional networks (EAN) in patients with PD comorbidity.Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyAberrant reconfigurations of connectivity patterns between the mPFC and the EAN are distinct features of the PD + SSD comorbidity. © 2022 The Authors.  The somatic symptom disorder (SSD) is a neuropsychiatric condition characterized by excessive attention to physical symptoms that cause exaggerated concerns and emotional distress and, sometimes, highly disabling consequences.The high co‐occurrence of SSD in PD patients raises the possibility of overlapping pathophysiology. However, little is known about the neural correlates of SSD and their possible interaction with PD. Several studies have shown that the reduced activity of the medial prefrontal cortex (mPFC)—a region involved in reality monitoring,1H‐MRS) was used to measure the contents of GABA and glutamate + glutamine (Glx) within a volume of interest (VOI) centered on the mPFC. Resting‐state functional MRI (rs‐fMRI) was used to investigate functional connectivity between the 1H‐MRS VOI and the rest of the brain.The central hypothesis of our study is that SSD patients show dysfunctional neurotransmission within the mPFC and a functional network reconfiguration between the DMN and the EAN. We also test the presence of shared and individual effects of SSD and PD on mPFC neurotransmission and connectivity patterns that help explain the neural mechanisms of comorbidity in PD patients. To test this hypothesis, we used multimodal magnetic resonance imaging (MRI) to assess neurochemistry changes and variations of mPFC functioning. Proton MR spectroscopy  and was performed according to the Declaration of Helsinki and subsequent revisions. The study cohort included 18 PD patients with SSD (PD + SSD), 18 PD patients (PD), 13 SSD patients who did not exhibit any other neurological comorbidity in a 5–7 years follow‐up (SSD), and 17 healthy control (HC) subjects. All participants gave written informed consent and were enrolled at the Neurology Clinic of the University “G. d'Annunzio” of Chieti‐Pescara, Italy.The United Kingdom (UK) Brain Bank Criteria were used for the diagnosis of PD.All participants underwent semi‐structured interviews performed by a rater blinded to SSD diagnosis. The interviews were structured on the DSM‐5 and assessed somatic complaints using examples and a checklist exhibited to patients and caregivers.1‐weighted turbo field‐echo sequence . T2‐weighted fluid attenuation inversion recovery images were also acquired to perform a neuroradiological evaluation.MRI data were collected with a Philips Achieva 3 Tesla scanner . Structural images were acquired using a 3‐dimensional T1H‐MRS VOI was centered on the mPFC  × 3.0 (left–right) × 3.0  cm3. An experienced MRI technician accurately placed the MRS VOI on the mPFC, in line with the seminal study on the DMN by Raichle and colleagues.A PFC Fig.  and acqu2*‐weighted echo‐planar sequences . For each subject, two runs of 300 functional volumes consisting of 21 trans‐axial slices were acquired with a TR of 1100 ms. Participants were instructed to lie still and keep their eyes closed during acquisition.Resting‐state blood oxygen level dependent fMRI data were acquired using gradient‐echo T1‐weighted images were analyzed using the “recon‐all ‐all” command line to obtain the automated reconstruction and labeling of cortical and subcortical regions (FreeSurfer 6.0).T1H‐MRS VOI and co‐register it on the anatomical image. Volumes and masks of grey matter (GM) and white matter (WM) within the 1H‐MRS VOI were obtained by combining the outputs of “recon‐all” (FreeSurfer) and “fslmaths/fslstats” (FMRIB Software Library) command lines. All the generated images were visually assessed to validate the positioning of the MRS voxel and evaluate the output of tissue segmentation. 1H‐MRS outcomes were shown as ratios of metabolites/tCrGANNET, a MATLAB‐based tool,1H‐MRS VOI, which encompasses the left and right GM within the mPFC, was used as a “seed region” for FC analysis using FreeSurfer‐Functional Analysis Streamhttp://surfer.nmr.mgh.harvard.edu/fswiki/FsFastFunctionalConnectivityWalkthrou). Preprocessing included motion and slice timing corrections, masking, registration to the structural image, sampling to the surface, and surface smoothing by 5 mm. Surface sampling of time series data was carried out onto the surface of the left and right hemispheres of the “fsaverage” template of FreeSurfer. Therefore, although the time series data were sampled onto fsaverage, the FC seeds were derived from the individual anatomy. Nuisance regressors were obtained for each participant by extracting the echo‐planar imaging (EPI) average time courses within the ventricle mask and the WM mask . These regressors and the motion correction parameters were eliminated from the EPI time series. Temporal band‐pass filtering (0.01 < Hz < 0.1) was applied to restrict the analysis on this frequency range. Because of T1 saturation effects, the first four rs‐fMRI time points were discarded from the analysis. Volumes for which the framewise displacement value (FD) is superior to 0.5 mm were removed. The mean signal time course within the seed region was used as a regressor to assess the pattern of FC. Using the “selxavg3‐sess” command, we performed the first‐level analysis , including the computation of the Pearson correlation coefficient  between the time series of the seed and the other voxels. The obtained correlation maps were then converted to Z‐score maps before entering the second‐level analysis . The “isxconcat‐sess” command was used to create a “stack” of maps from all study participants. For a qualitative assessment of whole‐brain patterns of mPFC connectivity in each group, the mri_glmfit command was used to calculate voxelwise maps representing correlation values averaged across subjects of each group. Yeo's functional atlas was used to label clusters of between‐group differences or within‐group correlations. For each participant, the global connectivity strength of the 1H‐MRS VOI was calculated in the left and right hemispheres by averaging the Z‐score from each voxel contained in the brain.The GM mask within the 2 test evaluated group differences in sex. A three‐way 2 × 2 × 2 ANOVA  was applied to test the between‐group differences and interaction effects among the three factors . Significant results are shown on statistical maps and adjusted by setting a cluster‐wise threshold at P‐corrected <0.05.P < 0.001.1H‐MRS VOI and cortical targets, which were obtained by comparing non‐SDD (HC plus PD groups) and SSD (SSD plus PD + SSD groups) participants. Sex, GABA, and age were included as independent variables. Spearman's correlation was used to investigate the relationships of MRI metrics with Symptom Questionnaire (SQ) scores.On the basis of data distribution, parametric analysis of variance (ANOVA) or nonparametric Kruskal‐Wallis tests evaluated group differences in demographic, imaging outcomes, and clinical data. Between the two PD groups, Mann–Whitney test verified the presence of significant differences in the UPDRS‐III, H&Y scores, and disease duration. A χF3,65 = 0.334, P = 0.801), educational levels , MMSE , and FAB  scores. PD disease duration , as well as the scores of UPDRS‐III  and H&Y  scales, did not differ between PD groups. A significant difference among groups was found for sex , and the PD group had a preponderance of males . Fluid‐attenuated inversion recovery (FLAIR)‐image assessments revealed no altered radiological findings among participants.The demographic, clinical, and imaging features of the study participants are shown in Table 1H‐MRS VOI are shown in Table The imaging‐based features of the P < 0.001), but not of PD (P = 0.909) or sex (P = 0.064), increased the levels of GABA+/tCr .The presence of SSD  among groups.Age did not significantly affect variations of GABA+/tCr  and the Glx/Cr levels  did not differ among groups.The GM volume within the MRS VOI , the enhanced connectivity effect was selectively observed in regions of the DMN    Fig. . No signThere was no significant correlation between the SQ test scores and the MRI metrics.F8,65 = 1566, P = 0.156). Moreover, the head movement amplitude (measured with the FD) did not differ between the four groups . Finally, no significant changes or interaction effects in cortical thickness were found among groups.Additional control analyses revealed that no influence of SSD, PD, and sex on the global connectivity  exhibited higher GABA+ levels within the mPFC. Therefore, the present study indicates that the GABAergic imbalance appears to be a general feature of SSD, independently from PD comorbidity. Moreover, the SSD cohort showed distinct patterns of enhanced functional connectivity of the mPFC with different networks, depending on the presence or absence of PD comorbidity. Whereas SSD patients increased connectivity with other regions of the DMN, SSD + PD subjects exhibited increased connectivity mainly with areas of the EAN.In the present study, we investigated the neurochemical properties and functional connectivity of the mPFC in separate groups of SSD + PD, PD, SSD, and HC participants. In line with our previous 1H‐MRS data, suggests that the imbalance of the GABAergic system alters the cortical excitatory/inhibitory equilibrium and could generate maladaptive functional network interactions. These changes provide a shared pathological framework for several neuropsychiatric conditions like anxiety, depression, and psychosis.GABA plays a crucial role in shaping cognitive functioning. Recent evidence, combining fMRI and 1H‐MRS is a non‐invasive tool that quantifies GABA levels in the brain. It is worth noting that the 1H‐MRS signal detects total, rather than synaptic, GABA levels,In line with this notion, in the SSD patients, we found increased mPFC functional connectivity with the DMN and frontoparietal components of the EAN . In a few cases, patients were also assessed by more in‐depth neuropsychological evaluations that ruled out the presence of MCI and confirmed a normal global cognition. Third, the sample size, especially for the SSD cohort, was relatively small for a cross‐sectional rs‐fMRI study. However, we would like to stress that this is the first multimodal MRI protocol that combines high‐resolution MRI, proton MR spectroscopy, and rs‐fMRI in SSD and PD subjects. The application of such a multimodal MRI protocol to a clinical population is very complex. It requires higher degrees of compliance by participants because of the long duration of scan time. Furthermore, we opted for an experimental design that included clinically selected cohorts, including patients with a de novo diagnosis of SSD. Fourth, the orbitofrontal cortex is an area known to be sensitive to EPI geometrical deformations. To address this potential issue, slice angulation was optimized to minimize the impact of in‐plane susceptibility gradients and reduce EPI distortions during data acquisition. Moreover, parallel imaging (sensitivity encoding [SENSE] factor = 1.8) was used to shorten the readout time. We recognize that BIn conclusion, increased GABA levels were found in SSD patients with and without PD. Aberrant reconfigurations of connectivity patterns across the executive/attentional network and the absence of hyper‐connectivity with the DMN are distinct features of PD patients who also exhibit SSD. Our results and the current experimental evidence support the notion that longitudinal assessments are needed to verify whether specific mPFC neurochemical and functional alterations exhibited by SSD‐PD subjects can be used to predict worsening of clinical conditions or incoming dementia.S.D.P. serves as academic editor of Scientific Reports, Behavioral and Brain Functions, and Medicine. S.D.P. was supported by research funding from Search for Excellence program from UdA. M.O. has served on the scientific advisory boards of GlaxoSmithKline, Novartis, Lundbeck, Eisai, Valeant, Medtronic, and Newron; has received speaker honoraria from Zambon, the World Parkinson Congress, the Movement Disorder Society, and the Atypical Dementias congress; publishing royalties from Springer; was an invited guest and lecturer for the Mental Disorders in Parkinson Disease Congress; serves on the editorial board of Medicine  and Frontiers in Neurology; has been employed as a speaker for Boehringer Ingelheim, GlaxoSmithKline, UCB, and Zambon; and has received research support from the Italian Ministry of Health and the Italian Ministry of Education. S.L.S. serves as associate editor of Frontiers in Neuroscience, Frontiers in Psychiatry, PlosOne, and Scientific Reports. He is supported by non‐profit agencies .(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.S.D.P.:1A, 1B, 1C; 2A, 2B; 3AR.F.: 1B, 1C; 3BP.C.: 1CA.F.: 1C; 3BR.A.E.: 3BC.S.: 2A, 2C; 3BM.R.: 3BS.L.S.: 1A, 1B; 2C; 3AM.O.: 1A, 1B, 3AAppendix S1 Supporting informationClick here for additional data file.


As the studies regarding the brain metastasis (BM) of pulmonary large cell neuroendocrine carcinoma (LCNEC) are insufficient, the present research aims to describe the risk factors and prognostic factors that are related to cancer‐specific survival (CSS) for LCNEC patients with BM.The data of LCNEC patients between January 2010 and October 2018 were obtained from the SEER database. Binary logistic regression analyses were utilized to screen the possible risk factors related to BM. Prognostic factors for LCNEC patients with BM were indentified by Cox regression analyses. Moreover, a nomogram was established to predict the 6‐, 12‐, and 18‐month CSS rates. The concordance index (C‐index), receiver operating characteristic (ROC) curves and calibration curves were utilized to assess the discrimination and reliability of the model. Clinical decision curves (DCAs) were used to evaluate the clinical benefits and utility of our model.Totally, 1875 patients were enrolled, with 294 (15.7%) of them having BM at diagnosis. Multivariate logistic regression analyses revealed that patients with age < 65  and N2 staging (OR = 1.775) had a greater chance of developing BM. Age , T staging , N staging , liver metastasis (HR = 1.410), primary site surgery (HR = 0.581) and chemotherapy (HR = 0.452) were independent prognostic factors for LCNEC patients with BM. A nomogram prediction model was constructed by incorporating these factors. Using the C‐index, calibration curves, ROC curves, and DCAs, we found that the clinical prediction model performed well.We described the risk factors and prognostic factors that were associated with CSS for LCNEC patients with BM. The related nomogram was established and validated to help clinicians formulate more rational and effective treatment strategies. This is the first large population study for LCNEC patients with BM. The related prognostic model based on these factors can guide clinical treatment decisions and prognostic judgments. A total of 1875 LCNEC patients between January 2010 and October 2018 were obtained. The inclusion criteria were: (1) pathological type: large cell neuroendocrine carcinoma (ICD‐O‐3 histologic type: 8013/3); (2) morphology site: lung and bronchus; and (3) complete information about T and N staging. In contrast, the exclusion criteria were (1) the data on survival, follow‐up duration and cause of death were absent or not correct; (2) diagnoses were merely finished on the foundation of autopsy outcomes or death certificates; (3) several primary cancers; (4) metastatic status was missing/unknown. According to the presence or absence of BM at diagnosis, we divided the cases with no metastasis of brain into the non‐BM group (n = 1581) and those with brain metastasis into the BM group (n = 294). The flow chart of selection is illustrated in Figure 2.2Four variables were extracted according to demographic characteristics, including age at diagnosis, gender , race , and marital status at diagnosis (married or unmarried). Eight variables were extracted according to cancer characteristics, including primary sites , laterality , T staging , N staging , bone metastases (no or yes), liver metastases (no or yes), lung metastases (no or yes) and AJCC seventh edition staging . Three variables were extracted according to treatment regimens, including primary site surgery (no/unknown or yes), radiotheraphy (no/unknown or yes) and chemotherapy (no/unknown or yes). Cancer specific survival (CSS) is considered to be the time from diagnosis to death due to LCNEC. In this article, CSS was utilized as the main endpoint.2.3p < 0.05 in the univariate logistic regression analyses were included in multivariate logistic regression analyses. Survival differences were evaluated by the Kaplan–Meier method and Log‐rank test. The prognostic factors with significant differences related to CSS in univariate Cox regression analyses were verified by multivariate Cox regression analyses. The nomogram was then built by the ‘rms’ package in the R software based on independent prognostic factors. The discrimination degree of the nomogram was assessed via the concordance index (C‐index) and receiver operating characteristic (ROC) curves. At the same time, the calibration degree of the nomogram was tested by drawing calibration curves to ensure the accuracy and reliability. Additionally, clinical decision curves (DCAs) were used to evaluate the clinical benefits and utility of our model. This study used the SPSS Statistics software 25.0 to perform the chi‐square test, univariate logistic regression analysis, multivariate logistic regression analysis, survival analysis, univariate Cox regression analysis and multivariate Cox regression analysis. Calibration curves, ROC curves and DCAs were drawn using the R language software 4.1.3. p < 0.05 was considered statistically significant.The basic clinicopathological data of each group were analyzed by the chi‐square test to show the differences between the non‐BM and BM groups, which were displayed as frequencies and proportions (%). Univariate logistic regression analyses were utilized to screen the possible risk factors related to BM. The variates with 33.1p < 0.001). Statistical analysis revealed that remarkable diversities existed in T and N staging between BM and non‐BM patients (p < 0.001). What's more, the BM group had more bone metastasis (22.8% vs. 12.8%), liver metastasis (23.5% vs. 14.7%) and lung metastasis (17.0% vs. 10.4%) compared with non‐BM group (p < 0.001). In terms of treatment, BM patients had less primary site surgery  and more radiotherapy . Additionally, the distribution of gender, race, marriage, primary site, laterality and chemotherapy was not associated with statistically significant outcomes (p > 0.05). The baseline features are presented in Table Totally, 1875 patients were enrolled, and 294 (15.7%) of them were in the BM group while 1581 (84.3%) of them were in the non‐BM group. The BM group was significantly younger (51.7% vs. 39.5%) than the non‐BM group (Risk factors for developing BM.p < 0.05), while those with T1 staging  had a lower incidence of BM (p > 0.05). The details are displayed in Table The clinical characteristics of age, gender, race, marriage, primary site, T staging and N staging were studied via univariable logistic regression analyses. Then the risk factors that might be related to BM were involved in multivariable logistic regression analyses. Eventually, the outcomes revealed that patients with younger age  and N2 staging  had a higher incidence of BM (3.2p < 0.001). Therefore, LCNEC patients with BM often exhibited unfavorable outcomes. The concrete outcomes of the median survival are presented in Table p < 0.05). Subsequently, multivariable Cox regression analyses indicated that an increasing age , T staging > T0 , N staging > N1  and liver metastases (HR = 1.410) were independent poor prognostic factors . On the other hand, primary site surgery (HR = 0.581) and chemotherapy (HR = 0.452) were independent favorable prognostic factors . The complete outcomes are presented in Table As presented in Figure 3.3Based on the 6 aforementioned prognostic factors, we established a CSS nomogram to forecast the survival probability of LCNEC patients with BM, as shown in Figure 4LCNEC is a highly aggressive malignancy prone to brain metastasis.Substantial literatures indicated that younger NSCLC patients were more prone to brain metastasis.In terms of prognostic factors in LCNEC patients with BM, several previous studies suggested that age > 65 years was related to poor prognosis.Nowadays, the standard therapeutic regimen for LCNEC patients with BM is still uncertain.As a visual tool for cancer prognostic assessment, the nomogram has been used to evaluate the prognosis of LCNEC patients and demonstrates good predictive value. However, the model that can forecast the prognosis of LCNEC patients with BM has not been developed yet. In this study, age, T staging, N staging, liver metastases, primary site surgery and chemotherapy were incorporated into the prediction model according to the outcomes of multivariable Cox regression analyses, and a nomogram was established. The C‐index and AUC were high and the calibration curves for the 6‐, 12‐, and 18‐month CSS rates showed good consistency, which revealed that the model had satisfactory discrimination and calibration. Therefore, it has certain value for clinicians to judge the prognosis of LCNEC patients with BM.However, there are some deficiencies. First, as our study utilized retrospective data from the SEER database, the results require the substantiation from more prospective trials. Second, the data on smoking status, comorbidities, performance scores, targeted therapies and immunotherapies were absent due to the constraints of the SEER database, which might affect survival results. Third, although the predictive model established in this study showed good accuracy and clinical applicability, patients were not divided into modeling groups and validation groups for model verification because the number of cases in some subgroups was too small. Eventually, as we did not have sufficient data from other sources due to the rarity of BM, external validation is required to realize further corroboration in the future.5Our study described the risk factors and prognostic factors that were associated with CSS for LCNEC patients with BM. The related nomogram was established and validated to help clinicians formulate more rational and effective treatment strategies.Xiaoyun Chen: Writing – original draft . Yedong Huang: Writing – original draft . Fangrong Chen: Formal analysis . Hui She: Writing – review and editing . Xiangqi Chen: Writing – review and editing .This research was supported by the Science Technology Innovation Joint Project Foundation of Fujian Province (2018Y9038) and Fujian provincial health technology project (2020CXB016).The authors declare no conflict of interest.


As previously reported, impairment of left ventricular global longitudinal strain (LVGLS) is associated with myocardial fibrosis, arrhythmias, and heart failure in hypertrophic cardiomyopathy (HCM) patients.This study aimed to estimate the association between LVGLS measured by echocardiography and major adverse cardiovascular events (MACE) in patients with HCM.Pubmed, Embase, Scopus, and Cochrane Library databases were systematically searched for evaluating the difference of LVGLS between MACE and non‐MACE and the relevance of LVGLS and MACE in HCM patients, mean difference (MD), and pooled hazard ratios (HR) with 95% confidence interval (CI) were calculated. Publication bias was detected by funnel plots and Egger's test, and trim‐and‐fill analysis was employed when publication bias existed.p < .001; I2 = 0, p = .48). In the pooled unadjusted model, LVGLS was related to MACE  and there is a mild heterogeneity, and sensitivity analysis showed stable results. In the pooled adjusted model, LVGLS was related to MACE . Egger's tests showed publication bias, and trim‐and‐fill analysis was applied, with final results similar to the previous and still statistically significant.A total of 13 studies reporting 2441 HCM patients were included in this meta‐analysis. Absolute value of LVGLS was lower in the group of HCM with MACE (MD = 2.74, 95% CI: 2.50–2.99, The meta‐analysis suggested that impaired LVGLS was associated with poor prognosis in HCM patients. The left ventricular ejection fraction (LVEF) is one of the most commonly used cardiac function parameters in clinical practice. However, in HCM patients, the thickening of the ventricular wall indirectly causes the narrowing of the heart cavity, so that LVEF can remain within the normal range despite impaired left ventricular systolic function.22.1A systematic search of Pubmed, Embase, Scopus, and Cochrane Library databases was conducted until May 1, 2022. The search terms were as follows: echocardiography, ultrasound, global longitudinal strain, GLS, longitudinal strain, strain, speckle tracking, and HCM.2.2Inclusion criteria: (1) HCM diagnostic criteria: The largest left ventricular wall thickness ≥15 mm, and increased load‐induced myocardial thickening such as hypertension, aortic stenosis, or congenital subaortic septum needs to be excludedExclusion criteria: (1) review, case reports, experiments on animals, comments, editorials, conference abstract, duplicate publications; (2) age <16; (3) the number of cases is less than 10; (3) non–English language literature.2.3Basic information for the included articles including author, publication years sample size, study design, age, gender, LVEF, and LVGLS. Means and standard deviations of LVGLS in the MACE and non‐MACE groups, as well as the unadjusted and adjusted HR with 95% CI, were extracted from the included studies. Newcastle–Ottawa Scale (NOS) was adopted to evaluate the quality of the included publications. All data were extracted independently by two authors.2.4The main outcome was MACE, including composite death and any cardiovascular events . Heart failure was defined as NYHA class III or IV with new or worsening symptoms of heart failure, including hospitalization for heart failure.2.5p < .05 considered to be statistically significant.The effect estimates were reported as mean difference (MD) of LVGLS among MACE and non‐MACE groups and HR with 95% CI, which was pooled from unadjusted and adjusted model effect estimates from the included studies, and with I‐squared (I2) statistic and Cochrane Q‐statistic were used to evaluate heterogeneity among included studies, I2 > 50% or p < .05 indicated the existence of heterogeneity, and a random‐effect model would be applied. Sensitivity analysis would be employed additionally.The p > .05. The trim‐and‐fill analysis was employed when publication bias existed. All statistical analyses were performed by Stata 15.1 software.Publication bias was detected by funnel plots and Egger's test. We concluded that there was no publication bias when the included literature was evenly and symmetrically distributed on both sides of the vertical axis of the funnel plots, and Egger's test showed that there was no publication bias when 3After carefully reading the full text, a total of 13 studies reporting 2441 HCM patients were included in this meta‐analysis,3.1p < .001; I2 = 0, p = .48), as is shown in Figure This set of analyses included 11 articles in which we extracted and combined the mean and standard deviation of LVGLS in MACE and non‐MACE groups from the included articles. Absolute value of LVGLS was lower in the group of HCM with MACE , and therefore a random‐effects model was adopted, showing that impaired LVGLS significantly increased the risk of MACE  , with no significant heterogeneity   was significantly reduced after removing the article of Vergé et al.  to , and found that heterogeneity (4p = .273).In the first part of the analysis, the funnel plot was symmetrical as shown in Supporting Information: Figure p = .033, 0.025) , pooled HR = 1.122, 95% CI: 1.083–1.164, p < .001 (adjusted model).In the second part of the analysis, the funnel plots of the unadjusted and adjusted models were both asymmetric (Supporting Information: Figure 5A total of 13 studies with 2441 patients were included in this study. The first set of analyses showed that LVGLS in HCM patients with MACE was significantly impaired. In the second part, we analyzed the correlation between LVGLS and MACE, and the unadjusted model included 10 articles with mild heterogeneity, therefore the random‐effects model was used, and then sensitivity analysis was performed by excluding articles one by one, finding that the heterogeneity was reduced after removing the article by Vergé et al.It is well known that LVGLS is superior to LVEF in detecting early left ventricular systolic dysfunction, so the application of LVGLS in the clinical practice of HCM has been a research hotspot. The studies of Haland and colleagues,Publication bias tests showed that although publication bias was present in the second set of analyses in both adjusted and unadjusted models, and further trim‐and‐fill analysis considered possible missing articles, the final results remained significant after filling, suggesting that publication bias had little effect on our results. Considering these findings, we believe that impaired LVGLS plays a strong prognostic role in HCM patients.In addition, it has been shown that longitudinal strain is highly reproducible and outperforms circumferential and radial strain in detecting early myocardial dysfunction.In conclusion, 2D‐STE not only detects LV systolic dysfunction at an early stage but also plays an important role in predicting poor prognosis in patients with HCM. This finding may contribute to better risk stratification of patients with HCM and has considerable clinical value.6This meta‐analysis has several limitations. First, the predictors used in the multivariate adjustment varied across studies. Second, a wide variety of endpoints were included. Finally, in the included studies, we did not perform subgroup analyses due to insufficient information.7LVGLS measured by 2D‐STE is a powerful and independent predictor of adverse events in patients with HCM.The authors declare no conflict of interest.Supporting information.Click here for additional data file.


The prevalence of occult hepatitis B infection (OBI) among Iranian liver transplant recipient patients has not been explored yet. The present study aimed to determine the OBI prevalence among Iranian liver transplant recipients.This study encompassed 97 patients having undergone liver transplantation due to several clinical backgrounds in the Liver Transplantation Center, Tehran, Iran. After serological evaluation, two different types of PCR methods were applied for amplification of HBV DNA, followed by the direct sequencing of whole hepatitis B virus (HBV) surface genes.At the time of admission, none of the patients were positive for HBsAg. However, 24 (25%), 12 (12.3%), and 5 (5.1%) cases were positive for anti‐HBc, hepatitis C virus (HCV), and hepatitis delta virus (HDV) antibodies, respectively. Moreover, two males were positive for OBI (2.1%). Both were positive for anti‐HBc and negative for anti‐HBs, anti‐HCV, and anti‐HDV. HBV‐related cirrhosis was the underlying reason for their liver transplantation. HBsAg sequences revealed no amino acid substitution.The prevalence of OBI in the Iranian liver transplantation patients was relatively low. Future longitudinal studies with a larger sample size are suggested to explore the significance of this clinical finding, including the reactivation of cryptic HBV DNA, in liver transplant subjects. The aim of this study was to characterize the prevalence of occult HBV infection in a series of liver transplant recipients. The present study comprised 97 patients who underwent liver transplantation. HBV serologic and molecular assays were performed. The hepatitis B surface antigen (HBsAg) genes from HBV‐DNA‐positive samples were amplified and directly sequenced. At the time of presentation, none were positive for HBsAg. However, 24 (25%), 12 (12.3%), and 5 (5.1%) were positive for anti‐HBc, hepatitis C virus (HCV), and hepatitis delta virus (HDV) antibodies, respectively. Two males were positive for OBI (2.1%). Both were positive for anti‐HBc and were negative for anti‐HBs, anti‐HCV, and anti‐HDV. HBV‐related cirrhosis was the underlying reason for their liver transplantation. Both OBI samples belonged to HBV genotype D and subtype awy2. HBsAg sequences did not show any amino acid substitution. Due to its cryptic nature, OBI still retains the same pro‐oncogenic features. It may contribute to the acute exacerbation and development of hepatitis B virus (HBV) associated diseases such as liver diseases, cirrhosis, and hepatocellular carcinoma (HCC).22.1primary sclerosing cholangitis . Most of the patients were transplanted during the last 3 years. Blood samples were collected during 2017‐2018. The study was evaluated and approved by the Ethics Committee of the Tehran University of Medical Sciences. The patients' history for the HBV vaccination before the transplantation time was unknown, and the authorities assumed that the transplant recipients had not received the HBV vaccine before transplantation. According to the routine guidelines in this center, all LT candidates received polyclonal HBIG 10000 international unit (IU) intramuscularly immediately before transplantation, followed by 5000 IU for the first seven postoperative days. Then, the patients received 1000 IU for 4 weeks and then monthly to maintain 250 IU. All HbsAg‐positive patients also received Tenofovir (300 mg daily) before transplantation and after transplantation as long as anti‐HBs achieved 300 IU. Finally, all transplant patients received daily Prograf (6 mg), Cellcept (2 mg), and Prednisolon (10 mg).The present cross‐sectional study encompassed 97 patients undergoing liver transplantation at the Liver Transplantation Center, Imam Khomeini Hospital, Tehran, during 2005‐2018. They had the following clinical backgrounds as candidates for liver transplantation: cryptogenic cirrhosis , HBV‐related cirrhosis , HCV‐related cirrhosis , HBV/HCV‐related cirrhosis , cirrhosis due to autoimmune hepatitis , fulminant hepatitis , Budd‐Chiari , and 2.2The viral markers of HBV, including HBsAg, anti‐HBs, anti‐HBc, and anti‐hepatitis delta virus , were measured by the enzyme‐linked immunosorbent assay according to the manufacturer's protocol.2.32‐109 IU/mL [2‐9 log10] IU/mL, and the lower detection limit of the assay was 85 IU/mL. Those samples negative in primary screening by real‐time PCR were re‐checked for OBI using another HBsAg gene‐nested PCR approach, which was recommended by Taormina expert meeting on occult HBV infection.HBV DNA was extracted from 200 μL of the aliquot of serum using the Qiagen Mini Blood Kit (Qiagen) according to the manufacturer's instruction. Regardless of the serologic results, a quantitative real‐time PCR was applied for all subjects using Fast‐track diagnostics/SIEMENS kits (Luxembourg) following the manufacturer's recommendations. The dynamic range of the assay claimed by the manufacturer was 10The nucleotide sequences of the HBsAg encoding component were determined bilaterally by the 3130 Genetic Analyzer . The sequences were compared, and edited, and the extra sections were deleted with Chromas software. Finally, the sequences encompassing the 681 nucleotides of the gene encoding HBsAg were transferred to BioEdit software version 7.0.9 in FASTA format. Seven HBV genotype D‐matched sequences  to study the mutations in the HBsAg region. Genotyping was performed by the phylogenetic analyses for the reference sequences of the HBV genotypes A‐H. A maximum likelihood (ML) tree was created using the alignment of the HBsAg gene of the subjects by rooting with a Woodchuck hepatitis virus. The phylogenetic tree was generated with MEGA X software, and the genetic distance was calculated using Kimura's two‐parameter matrix.2.4Data were analyzed with the Statistical Package for the Social Sciences . The continuous variables were expressed as mean ± standard deviation or median, and the categorical variables were expressed as percentages.3P = .002). At the time of presentation, no case was positive for HBsAg; however, 24 (25%), 12 (12.3%), and 5 (5.1%) cases were positive for anti‐HBc, anti‐HCV, and anti‐HDV, respectively  and 40 42%) individuals were male and female, respectively. The participants' age ranged from 15 to 65 years old, with the mean age of 47.66 ± 11.71 for males and 38.72 ± 13.07 for females (% individ4One of the main clinical implications of OBI is usually observed in the setting of liver transplantation. In particular, livers from donors with OBI carry a risk of HBV transmission, with infection arousing in 25%‐95% of the liver grafts donated from patients being HBsAg negative and anti‐HBc positive.Two OBI patients in the present study were positive for anti‐HBc and negative for anti‐HBs. The hypothesis behind the low prevalence of OBI among Iranian liver transplant recipients remains elusive. However, several factors have been attributed to the evolution of HBV around the globe, of which the HBV genetic variations with the highest frequency have been the most underlying factor. Several HBV mutations within the “a” determinant of HBsAg have been reported in association with OBI.On the other hand, the HBV genotypes B and C are prevalent among Southeast Asian chronic HBV populations.5The prevalence of OBI among Iranian patients referred to one of the two Iranian referral centers for liver transplantation was relatively low. Future longitudinal studies are required to employ a larger sample size to explore the significance of this clinical finding, including the reactivation of cryptic HBV DNA, in liver transplant subjects.Study concept, design, and drafting of the manuscript: Seyed Mohammad Jazayeri and Mohsen Nasiri toosi; Acquisition of data and experimental analysis: Azam Khamseh, Vahdat Poortahmasebi, Azam Ghaziasadi, Saber Soltani, and Saeid Ghorbani; Interpretation of data: Ali Jafarian, Mehdi Norouzi and Narges Eslami.None of the authors declared any conflict of interest.Appendix S1Click here for additional data file.


With the widespread use of alectinib in patients with anaplastic lymphoma kinase (ALK)‐positive non‐small‐cell lung cancer (NSCLC), its cardiotoxicity has gradually emerged, including new‐onset sinus bradycardia (SB). However, the incidence, timing, severity, and risk factors of alectinib‐induced bradycardia remain unknown.From January 2020 to June 2022, 93 patients with ALK‐positive NSCLC treated with alectinib were enrolled in this retrospective analysis. These patients had heart rate (HR) recorded before and after alectinib administration. By reviewing electronic medical records and follow‐up, the HR changes of patients during medication were recorded. The potential risk factors associated with alectinib‐induced SB were explored.p < 0.001) and history of hypertension  were independent risk factors for alectinib‐related bradycardia.According to an HR cut‐off of 60 beats per minute (bpm), 47 patients (50.54%) experienced at least one recorded bradycardia. The mean HR of total participants before alectinib administration was 78.32  and after was 64.88 . The median maximum change in HR (range) for all patients was 11  bpm. For the bradycardia subgroup, the HR of most patients (76.60%) hovered around 50–60 bpm, and 61.70% of SB occurred within 3 months after alectinib administration. Multivariate analysis indicated that baseline HR (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.79–0.93, Alectinib‐induced bradycardia had a high incidence, appeared relatively early, and was reversible by dose reduction or withdrawal. To clarify the bradycardia associated with alectinib, 93 patients with anaplastic lymphoma kinase‐positive non‐small‐cell lung cancer treated with alectinib were enrolled in this retrospective analysis. The results showed that alectinib‐induced bradycardia had a high incidence, appeared relatively early, and was reversible by dose reduction or withdrawal. Baseline heart rate and history of hypertension were independent risk factors for alectinib‐related bradycardia. Alectinib, an oral, highly selective, second‐generation tyrosine kinase inhibitor (TKI), has dramatic efficacy in patients with anaplastic lymphoma kinase (ALK) rearrangement non‐small‐cell lung cancer (NSCLC).To elucidate the incidence, severity, and risk factors of alectinib‐induced SB, we conducted a retrospective cohort study. We reviewed the electrocardiograms before and after medication, recorded the timing and degree of bradycardia, and documented the intrinsic clinical characteristics hoping to identify risk factors that may predispose patients to bradycardia.This study was a single‐center, retrospective cohort study performed at the Tianjin Medical University Cancer Institute and Hospital (TJMUCH), Tianjin, China. For patients with ALK rearrangement NSCLC treated with alectinib at TJMUCH from January 2020 through June 2022, we conducted electronic medical records queries and phone follow‐ups after local ethics committee approval. Inclusion criteria were adults ≥18 years of age with ALK‐positive NSCLC receiving alectinib monotherapy. HR and recognized risk factors for cardiovascular disease were recorded across time. This retrospective analysis included only patients with available pre‐treatment HR and post‐treatment HR measurements. We looked through the electronic medical records to extract risk factors, including baseline clinicopathological characteristics, comorbidities, hematologic parameters, potential symptoms related to SB, and treatment response. Patients with incomplete medical records were excluded.The primary outcome was new‐onset bradycardia after alectinib initiation; patients with preexistent bradycardia at baseline were excluded. Bradycardia was defined as a resting HR <60 beats per minute (bpm). The patient's HR were obtained from an electrocardiogram (ECG), ECG monitoring, electronic equipment, etc. We collected the time of the first onset of SB, the lowest HR recorded postbaseline, and the degree of HR decline. Bradycardia was documented and graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (CTCAE). The secondary outcomes were participants discontinuing medication owing to disease progression, intolerance of side reactions, or death for any reason. Response Evaluation Criteria in Solid Tumors version 1.1 was used to evaluate tumor response.t‐test, Pearson's χ2 test, or the Mann–Whitney U test in an appropriate way. Independent variables with p < 0.1 in the analysis of difference that may increase the risk of alectinib‐induced bradycardia were estimated using logistic regression analysis. The PFS of the total population and subgroups was assessed using the Kaplan–Meier method. All analyses were conducted in SPSS software (version 25.0) and two‐tailed p < 0.05 was considered statistically significant.Continuous variables use the mean ± standard deviation (SD) or median (interquartile range [IQR]) and categorical variables use the frequency counts with percentages for descriptive statistics. Difference analyses of baseline characteristics and cardiac parameters between bradycardia and nonbradycardia groups were conducted using Student's 2. Fifty‐eight patients (62.37%) were female and 62 patients (66.67%) had a PS of 0 to 1 (Table n = 72) were still using alectinib. One patient received first‐line treatment with alectinib in stage I because of her advanced age and intolerance to surgery. Another patient started alectinib in stage I for preoperative adjuvant therapy because the tumor was too close to the hilum for surgery.From January 2020 to June 2022, 170 patients with ALK‐positive NSCLC presented to TJMUCH. A total of 98 patients were previously or currently treated with alectinib monotherapy, and five of them were excluded due to incomplete medical records. The screening process is shown in Figure p < 0.0001), the mean lowest HR achieved (p < 0.0001), and the median time to maximum HR decrease (p < 0.0001) between patients who did and did not experience SB (Table p < 0.0001) (Table n = 29) who developed bradycardia within 3 months of alectinib initiation  experienced at least one recorded bradycardia. The mean HR of total participants before the alectinib was 78.32  and after the alectinib was 64.88 (SD 12.21) , history of hypertension (p = 0.014), abnormal baseline levels of white blood cell counts (p = 0.017), and decreased baseline HR (p < 0.001) were significantly related to alectinib‐induced bradycardia. Six clinical factors with p < 0.1 in univariate analysis were included in the logistic regression analysis. In a multivariate model (Table p < 0.001) and history of hypertension  remained related to bradycardia development. Abnormal baseline white blood cell counts enhanced the potential to develop SB during alectinib treatment, while in multivariate logistic regression analysis this difference was not statistically significant.We explored the potential risk factors of alectinib‐induced bradycardia. From Tables el Table , howeverp = 0.687) (Table p = 0.429).To evaluate alectinib's clinical efficacy in our cohort study, we followed up with the enrolled patients and collected information on survival data. As shown in Table 7) Table . The difThrough the analysis of longitudinal changes in HR after alectinib initiation, our study revealed that alectinib‐induced bradycardia had a high incidence, occurring in nearly half of patients, appeared relatively early, generally within 3 months of medication, and was reversible by dose reduction or withdrawal. Continuation of alectinib did not result in a progressive decrease in HR, indicating bradycardia was not cumulative toxicity. Because of its remarkable clinical efficacy, alectinib has an increasing number of users with a long duration of drug use. Our observation comprehensively described alectinib‐induced bradycardia, which is of particular significance given the absence of early markers to evaluate cardiotoxicity.Patients with lower HR showed a higher likelihood of developing alectinib‐related bradycardia in our cohort. Ou et al. reported similar conclusions in a study of risk factors for crizotinib‐related bradycardia, indicating that HR <70 bpm was an independent risk factor of SB.The SB grading criteria specified by the CTCAE are not based on measured HR values but rely on symptoms and the need for hospitalization. A total of 47 participants reported alectinib‐related SB: 65.96% grade 1, 29.79% grade 2, and 4.26% grade 3. Chest tightness, fatigue, and edema are common symptoms in patients with cardiac dysfunction. In our cohort, 19 patients (20.43%) showed chest tightness, 44 patients (47.31%) showed fatigue, and 41 patients (44.09%) showed edema. Univariate analysis showed that chest tightness and fatigue are statistically associated with bradycardia. However, the causal relationship between chest tightness, fatigue, and bradycardia remains unclear. Nowadays, physicians are not adequately aware of the cardiotoxicity of alectinib and often neglect regular ECG monitoring during drug administration. This finding also suggests that when patients complain of chest tightness and weakness, in addition to considering the disease itself, we should also pay attention to the occurrence of alectinib‐induced cardiotoxicity. In our research, alectinib‐induced bradycardia appeared to be reversible, and three patients had a rapid return to normal heart rate after discontinuation of the drug for severe bradycardia. Similarly, a recent case report also showed that a patient with NSCLC developed bradycardia after the application of alectinib, and the patient returned to sinus rhythm after withdrawal of the drug.Alectinib‐induced bradycardia provides further evidence to prove the association between alectinib initiation and adverse cardiovascular outcomes. Cardiovascular toxicity associated with ALK inhibitors has caught the attention of investigators. To evaluate the relationship between ECG parameters and corresponding drug concentrations, Morcos conducted a retrospective analysis of two clinical studies of alectinib, NP28761 and NP28673, pointing out that alectinib‐related cardiovascular toxicity was dose‐irrelevant, and the average HR dropped by 11–13 bpm in the 2 weeks after medication.p = 0.355). Due to the available data on betablockers and non‐dihydropyridine calcium channel blockers (CCBs) being limited, physicians should be cautious about combining alectinib with such agents. There is no consensus on the exact mechanism of ALK‐TKI‐induced arrhythmia in patients with advanced NSCLC. To elucidate the molecular mechanisms of TKI‐related arrhythmia, additional mechanistic and prospective studies are required to reveal undiscovered common targets and common biological pathways.At present, there is no consensus on the pathogenesis of ALK inhibitor‐related arrhythmia, and plausible mechanisms that involve ion signaling pathways, endocrine regulation, and drug metabolism may underlie this condition. Ou et al. pointed out that crizotinib‐induced arrhythmia may be associated with the antagonism of L‐calcium channels, the effect of epithelial‐mesenchymal transition, and the function of sinoatrial and atrioventricular nodes.Several limitations should be recognized. Our research is a single‐center retrospective cohort study with limited participants and nonuniformly available data. Due to the lack of a pre‐specified, standardized cardiovascular monitoring and follow‐up protocol, we are missing changes in ECG parameters other than HR, and the potential to recognise additional events was limited. Selection bias may exist in patients who received at least one ECG after alectinib administration. Patients who accepted more cardiovascular monitoring had higher odds of detecting medication‐related arrhythmia. Electrocardiogram follow‐up times varied, potentially leading to extra detection bias. Furthermore, given the insufficient awareness of the severity of bradycardia, some SB and the management after SB are possibly undocumented in medical records. Finally, some research variables have not been clearly defined, such as the classification of sleep and diet.In summary, alectinib is linked to a significantly raised risk of newly developed SB, which is reversible and dose‐independent. Although alectinib‐related bradycardia is mostly asymptomatic and not life‐threatening, there are patients who encounter dose reduction, drug discontinuation, or even death due to severe bradycardia. The newly prospective combination of alectinib and the anti‐angiogenic agent bevacizumab has obtained positive results, along with the risk of cardiovascular adverse events increasing.Peng Chen and Dong‐qi Yuan were responsible for the conception and design of the study. Dong‐qi Yuan, Fu‐yi Zhu, Ran Zuo, Yu Wang, and Geng‐wei Huo were responsible for collecting data. Dong‐qi Yuan, Jin‐fang Cui, and Ping Yue analyzed the data. All authors were responsible for the revision and approval of the final version of the manuscript.The authors declared no conflicts of interest for this work or regarding the publication of this paper.This work was supported by funding from the Tianjin Major Disease Prevention and Control Science and Technology Project, Tianjin Municipal Science and Technology Bureau (18ZXDBSY00050).


Several studies have explored the relationship between intratumoral microvessel density (MVD) and the risk of postoperative biochemical recurrence (BCR) in prostate cancer (PCa), although the results are contradictory. Therefore, we conducted a meta‐analysis to investigate the effect of MVD on BCR in PCa.We searched PubMed, MEDLINE, Science Direct/Elsevier, the Cochrane Library, CNKI, and EMBase databases from inception through January 2022, with no year or language restrictions, and used NOS guidelines to evaluate the quality of the 19 eligible studies. The derived hazard ratio (HR) and 95% confidence interval (95%CI) were used to assess each endpoint. Data synthesis was performed with RevMan to assess the prognostic value of MVD in PCa and its heterogeneity, while the publication bias was examined using STATA 16.0.p = 0.03; I2 = 83%), T1‐3 , T1‐4 .The subgroup analyses based on European and immunohistochemical antibody none‐factor VII were consistent with primary one. Sensitivity analysis excluding those studies judged to be at high risk of bias in T1‐2 showed a HR of 2.99 , demonstrating the robustness of risk estimates of MVD for the assessment of biochemical recurrence.Our meta‐analysis included 19 articles  on postoperative biochemical recurrence of PCa, among which, 3933 patients were pooled. The predictive ability of intratumoral MVD for different stages of PCa on BCR was T1‐2 (HR, 2.46; 95% CI, 1.08–5.58; Microvessel density is a predictor of BCR among patients with PCa, and earlier T stage PCa with a stronger MVD is associated with BCR. Further studies are needed to investigate neoangiogenesis in different T stages of PCa and whether MVD will be of benefit to the EAU‐recommended tool for biochemical recurrence risk assessment. Microvessel density is a predictor of biochemical recurrence among prostate cancer patients.Moreover,in earlier T stage PCa is, a stronger microvessel density is associated with biochemical recurrence. The three keywords used were PCa, microvessel density, and prognosis. PCa included “PCa,” “prostate tumor,” “prostate neoplasm,” and “prostate carcinoma”; for prognosis, “Prognos*,” “prognostic factor,” “outcome,” “survival” “PSA recurrence,” “PSA failure,” “predictor,” and “predict” were used; and for microvessel density, “mvd,” “microvessel densit*,” “microvessel count,” “neovascularization,” “microvascular densit*,” “vascularity,” “CD34,” “CD31,” “vwf,” and “vascular density” were used. We also retrieved citations from a manual search.2.2To access eligible articles, studies were required to meet certain inclusion and exclusion criteria.2.2.1Exploring the relationship between MVD and the risk of biochemical recurrence.Patients with PCa had not received neoadjuvant therapy or invasive biopsy before tumor resection.Classification of patients with PCa was based on TNM staging.MVD visualized by CD31, CD34, and Factor VII.MVD located in the primary tumor tissue .Evaluation of outcomes on MVD including BCR.Include cohort studies and randomized controlled studies.2.2.2Meeting abstracts, reviews, descriptive studies, case reports, commentaries.Sample size <20.Inadequate information on HR calculations and data synthesis.Non‐English language2.3The information for each study was extracted independently by two investigators (Jinze Li and Xingyu Xiong) with a standardized data form including the following items: first author, publication year, patient source, age, follow‐up, disease stage, specimen acquisition, and results. Among these articles, HR from multivariate analysis was preferred, followed by univariate analysis and Kaplan–Meier survival curve. The primary endpoint was biochemical recurrence, and the secondary endpoint was tumor progression. For studies lacking HR, we calculated the HR using survival curves as described by Tierney.2.4The RoB in the selected studies was assessed by two authors using the Newcastle‐Ottawa Scale (NOS) tool, which assesses selection, performance, detection, attrition, reporting, and other sources of bias (Supplementary Table 2.5p < 0.05 (two‐sided).In assessing the BCR for PCa of T1‐2, T1‐3, and T1‐4, the log HR and the standard error calculated from the published HR and confidence interval (CI) were retrieved. A meta‐analysis was conducted for each outcome using a random effect models for the predictive value of MVD. The relative predictive effects are presented as the HR and 95% CI.We planned to perform a subgroup analysis based on (1) ethnicity and (2) immunohistochemical antibodies none‐Factor VII. STATA 16.0 was employed to assess publication bias via a funnel graph and Egger's test. When publication bias existed, we used trim and fill method via STATA 16.0 to examine the stability of the findings. All statistical analyses were performed using Review Manager 5.4 software and STATA 16.0 software. Statistical significance was defined as 33.1We searched 72 articles, of which 34 were excluded during abstract reading. Thirty‐eight articles were full‐text reviews, of which 19 met our requirements, and each study source was extracted for data synthesis. The reasons for exclusion of articles are presented in Figure 3.2p = 0.0005), for T1‐3 were 2.38 , and the pooled HR (95% CI) for T1‐4 was 1.61 . The results are shown in Figure We performed statistical calculations among the 19 eligible studies associated with biochemical recurrence, including four studies for T1‐2 PCa, six for T1‐3 PCa, and nine for T1‐4 PCa. Individually, the pooled HR and its 95% CI for T1‐2 were 2.46  and 1.66  in T1‐3 and T1‐4, respectively. As shown in Figure We performed subgroup analysis with the following items: the patients' origin (European) and the antibody used to detect MVD (none‐Factor VII) in immunohistochemical staining. We aggregated the studies from three groups T1‐2, T1‐3, T1‐4) based on angiogenic markers (none‐Factor VII) to predict the BCR within HRs. As shown in Figure , T1‐4 ba3.3p = 0.002), which was consistent with the primary one, indicating that publication bias in T1‐3 did not generally change results.Publication bias was assessed using funnel plots and Egger's test with STATA 16.0. However, total number of articles of T1‐2 PCa was 4, there was a risk of overestimating the validity of the results of pubication bias in T1‐2 PCa. We only performed publication bias on T1‐3 and T1‐4. The funnel plots revealing evidence of potential publication bias are displayed in Figures 3.4I2 = 38%, p = 0.0001) in the T1‐2 group.Overall, a sensitivity analysis was conducted, in which one study was removed at a time, and the results are presented in Figures 4Until now, predictors related to BCR can be roughly divided into two categories: tumor biology including the pathological Gleason score and clinical variables including preoperative PSA level, tumor stage, seminal vesicle invasion, lymph node, and surgical margin status, and are widely used as risk factors for BCR, most of which are incorporated through the nomogram. Raisa et al. reported that their BCR nomogram, which included easily applicable variables, could be used to predict BCR within 12 and 24 months of RP in European patients who received RP.We performed a meta‐analysis to explore the ability of MVD to predict the risk of BCR in different stages of PCa. The results of the meta‐analysis demonstrate that, in general, MVD in cancer tissues is associated with postoperative BCR of PCa, but the value of risk prediction differs when considering patients at different clinical stages. For PCa in the T1‐4 population, MVD was associated with poor prognosis, with an HR of 1.61 (1.19–2.19). While only clinically localized prostate was included, the HR for BCR was 2.46 . Interestingly, the risk of PSA recurrence changed when patients were included in different clinical stages. As more higher‐stage patients are included, the HR for predicting BCR in PCa decreases; however, patients diagnosed with pathological stage T3‐4 are prone to undergo more aggressive treatment, such as chemical therapy and anti‐androgen therapy (ADT), after surgery. In contrast, most of the T1‐2 patient population merely undergo surgical resection or radiotherapy and rarely receive additional treatment after surgery, resulting in the patients with PCa in the T1‐2 population being at a higher risk of BCR.Elżbieta Łuczyńska observed that the expression of VEGF in pTNM3 and pTNM4 is significantly higher than that in pTNM1.However, from the perspective of tumor progression, angiogenesis is more intensive in early stage PCa confined to the fibrous capsule than in patients with locally advanced PCa, in which the cancer has breached the fibrous capsule and invaded surrounding tissues. The process of tumor vascularization is vital for the early stage of tumor growth and remains vulnerable to inhibitors. Weidner found that PCa tumor cells rarely enter the blood circulation and undergo micrometastasis before the primary tumor is fully vascularized, and tumor progression and metastasis require tumor cells to enter the bloodstream.Bevacizumab is a monoclonal drug targeting VEGF‐A, which is the main regulator of angiogenesis. Theoretically, bevacizumab can bind to VEGF‐A and interfere with the combination of VEGF‐A and its receptors, blocking the process of tumor angiogenesis and consequently delaying or even inhibiting tumor growth, invasion, metastasis, and other malignant behaviors. Bevacizumab has achieved good performance in the treatment of non‐small cell lung cancer, metastatic colorectal cancer, and breast cancer.Unlike the poor outcome of mCRPC treated with bevacizumab, bevacizumab achieved satisfactory results in clinically localized PCa. In a phase II clinical trial of neoadjuvant docetaxel plus bevacizumab in high‐risk localized patients with PCa, 29% of patients achieved a >50% reduction in tumor volume. It is encouraging that bevacizumab combined with neoadjuvant chemotherapy can reduce the tumor volume and decrease the difficulty of cancer resection.The discrepancy in the predictive value and efficacy of anti‐angiogenesis therapy in different stages of PCa suggests that tumor vascular development and response to antivascular therapy are highly associated with tumor progression. In addition to VEGF, PDGF, FGF, and other typical angiogenesis molecules, Boddy et al. claimed that androgens may regulate VEGF levels by activating HIF in androgen‐sensitive tumors.Currently, with numerous drugs targeting angiogenesis molecules, whether an angiogenesis‐targeted regimen can be a promising choice for PCa requires further exploration among different stages of PCa. The underlying mechanism may involve a complex interaction of angiogenesis‐related molecules and androgens in PCa at different clinical stages, resulting in different predictive values of MVD and discrepancies in the efficacy of angiogenesis‐targeted therapy.The conventional BCR stratification tool proposed by the EAU was based on the GS score, clinical stage, and preoperative PSA. Cooperberg5I2 = 0.0001) among T1‐2 group. Overall, after confirming no extra missing study, performing sensitivity analysis, the original results were considered to be convincing.We failed to perform publication on T1‐2 PCa. Only 4 studies on clinically localized PCa (T1‐2) were included, for publication bias, there is a risk of overestimating the validity of the results of publication bias.We were unable to conclude a quantitative relationship between MVD and PSA relapse time because the median MVD and follow‐up duration were highly heterogeneous among the included studies.6Microvessel density can predict postoperative BCR in different stages of PCa, and as tumor stage increases, the risk of BCR decreases. Whether MVD prediction can supplement existing EAU BCR risk stratification tools requires further research.Jinjiang Jiang contributed to choose research directions. Jinze Li,Xingyu Xiong, Lu Yang were responsible for literature retrieval. Jinze Li, Qiang Wei and Xingyu Xiong contributed to literature inclusion. Shiyu Zhang and Daqing Tan assessed the level of evidence. Jinjiang Jiang and Jinze Li finished the manuscript. All authors read and approved the publication of final manuscript.The authors declare that there are no conflicts of interest.The data that support the findings of this study are available from the corresponding author upon reasonable request.Not applicable.Figure S1Figure S2Figure S3Figure S4Figure S5Click here for additional data file.


Sorghum bicolor var. SS-77. Based on pilot experiment, 100 mg L−1 concentration of coumarin was applied to mitigate the negative effects of salinity on Sorghum, grown at 0, 100, and 200 mM NaCl under netted greenhouse conditions. Coumarin was applied to each salinity treatment in four different ways (i) non-primed control (NP), (ii) seed priming (COP), (iii) foliar application (COF), and (iv) a combination of seed priming and foliar application (COPF). Salinity stress significantly reduced the plant growth, biochemical attributes, and photosynthetic efficiency of Sorghum, whereas coumarin treatments  showed a significant increase (P< 0.01) in above-mentioned parameters at all salinities. Among all, the combined treatment (COPF) showed maximum increase in growth, biochemicals, photosynthetic pigments, antioxidant enzymes, and photosynthetic efficiency parameters. Therefore, it is suggested that a combination of seed priming and foliar spray of 10 mg L−1 coumarin is more suitable than their individual applications. It is an environment friendly and economically feasible approach that will be used to improve salinity tolerance of Sorghum and helpful to get considerable biomass from saline degraded lands to fulfill food, fodder, and energy demands of the ever-growing population.Secondary metabolites, such as phenolic compounds, play an important role in alleviating salinity-induced negative effects in plants. The present study focused on seed priming and foliar application of a potent phenolic compound, coumarin, to induce salinity tolerance in  Sorghum bicolor is a moderately salt tolerant, multipurpose C4 plant, widely cultivated in arid and semi-arid areas for food, fodder, and biofuel purposes (+ and Cl−) resulting specific ion toxicity, osmotic stress, and oxidative damages, which in turn leading to nutritional, hormonal, and enzymatic imbalances. Additionally, salinity stress reduced photosynthetic performance by altering enzyme activities, destroying photosynthetic pigments, reducing leaf area, and inhibiting photosystem efficiency  responsible to damage various cellular components such as plasma membranes, proteins, lipids, and nucleic acids . To avoid the osmotic shock, NaCl concentration was increased gradually (50 mM NaCl per day) until the final concentration reached. The COU application in each salinity treatment was applied in four different ways, i.e., (1) non-primed control (NP), (2) seed priming (COP), (3) foliar spray (COF), and (4) a combination of seed priming + foliar spray (COPF) with six replicates each. The COP and COPF seeds were primed with 100 mg L−1 coumarin, whereas the NP and COF treatments remained unprimed. COF and COPF were sprayed with 100 mg L−1 coumarin three times during the experiment. First foliar spray was done at 20th day of seedling emergence and rests were done after 1-week interval of first spray. After 40 days of growth, plants were harvested and growth and biochemical parameters were measured.In our previous experiment, we used 50 and 100 mg L results , hence sa, chlorophyll b, total chlorophylls, and carotenoids (Fresh sample (0.25 g) of Sorghum leaves was ground with liquid nitrogen, homogenized in 5 ml of 80% acetone and centrifuged at least three times at 3,000 rpm for 10 min each. Supernatant then separated and absorbance was measured at 645, 663, and 480 nm to calculate the chlorophyll otenoids .Total anthocyanin content was estimated using fresh leaves (0.25 g) from each treatment, homogenized with 5 ml of 0.1 N methanol-HCl reagents, and centrifuged at 4,000 rpm for 10 min . Superna−2 s−1) was measured. Afterward, leaves were subjected to 10,000 photons (μmol m−2 s−1) light for 0.8 s to analyze the maximum fluorescence . Coefficient of photochemical quenching (qP) was calculated as (Fm′-Fs)/ was used to evaluate the photosynthetic performance of plants. Healthy fully expanded leaves from the third and fourth nodes were selected and adapted in dark for 30 min before measuring the lower range of the fluorescence Fo;  in whichence Fm; . Furtherence Fm; , quantumence Fm; . Non-phoence Fm; , was calFm′-Fo′; . PSII isFm′-Fo′; , ETR = P−1, 400 μl) solution was added, and the mixture was further incubated for 1.5 h at room temperature. Absorbance was recorded at 765 nm against the standard curve of gallic acid. Total soluble carbohydrates were estimated according to the method of Total phenolic content (TPC) was measured in dry plant material . Plant d2O2, 0.5 ml TCA extract was mixed with 0.5 ml potassium phosphate buffer  and 1 ml potassium iodide (1 M) and incubated in dark. After 10 min, the absorbance was recorded at 390 nm.Fresh sample (0.5 g) of Sorghum leaves was ground in liquid nitrogen, homogenized in 3% ice-cold trichloro-acetic acid (TCA), and centrifuged at 15,000 rpm for 15 min at 4°C . Supernag for 10 min at 4°C. Absorbance was recorded at 532 nm, 600 nm, and 450 nm.For estimation of MDA, 0.5 ml TCA extract was mixed with 0.5 ml 20% (w/v) trichloro-acetic acid containing 2-thiobarbituric acid (0.5%) in a capped glass test tube and placed in a water bath at 95°C for 30 min . The reaFresh samples (0.5 g) of Sorghum leaves were ground in mortar and pestle using liquid nitrogen and homogenized in 5 ml of potassium phosphate buffer . The solutions were centrifuged at 20,000 rpm at 4°C for 20 min. The supernatants were carefully transferred into Eppendorf tubes and stored at −40°C.Total soluble proteins were estimated according to the method described by −1 cm−1) was measured according to 2O2 and 100 μl of enzyme extract was placed in a quartz cuvette in a spectrophotometer, and decrease in absorbance was recorded at 240 nm for 1 min.Catalase (CAT) activity (extinction coefficient = 39.4 M−1 Cm−1) was estimated according to the method of 2O2, and 100 μl of enzyme extract was placed in a quartz cuvette in a spectrophotometer and linear decrease in absorbance was recorded at 290 nm for 1 min.Ascorbate peroxidase (APX) activity (extinction coefficient = 2.8 mM−1 Cm−1) was estimated according to the method of 2O2, and 50 μl of enzyme extract was placed in a quartz cuvette in a spectrophotometer and increase in absorbance was recorded at 470 nm for 1 min. The specific enzyme activities were determined by dividing the enzyme activity (unit mL−1 enzyme) of protein concentration (mg mL−1) of the respective plant samples, and presented as the unit mg−1 protein.Guaiacol peroxidase (GPX) activity (extinction coefficient = 26.6 mMp < 0.05) among treatments, and the ANOVA was performed by the least significant difference (LSD) test to compare the significance of priming and salinity treatments.The data are presented as the mean ± S.E. Statistical analyses were carried out using SPSS Ver. 20.0 for Windows . Two-way ANOVA and Tukey’s HSD test were performed to analyze the differences (p < 0.01) with increasing salinity. However, all COU applications  significantly increased (p < 0.01) the lengths and fresh and dry weights of shoot and root at all salinities as compared to the non-primed control. The highest increase in length and biomass were observed in the COPF treatment under both non-saline and saline conditions  significantly decreased (p < 0.01) with increasing salinity. However, COU application showed an increasing trend under saline conditions compared to their respective counterparts. Furthermore, carotenoids and anthocyanins were directly proportional to increasing salinity. However, anthocyanins and carotenoids increased to a greater extent in all coumarin treatments than the control. Anthocyanins and carotenoids were higher in the COPF treatment than the non-primed and other COU treatments at 200 mM NaCl  significantly decreased with increasing salinity and COU application did not help plants in improving Y(II), except COPF at 100 mM NaCl. The Y(NPQ) increased with increasing salinity, in both COU treated and untreated plants. The Y(NO) values were unchanged throughout the experiment .Salinity had an increasing effect on total soluble carbohydrates and phenols of Sorghum, that was further enhanced by COU applications. The maximum concentrations of carbohydrates and phenolic contents were observed in the COPF treatment, particularly at 200 mM NaCl ,B.2O2 contents were significantly (p < 0.01) increased with increasing salinity. The highest amount of both markers was observed at highest salinity of non-prime control plants. All COU treatments significantly (p < 0.01) reduced the MDA and H2O2 contents under both saline and non-saline conditions. The maximum decline was observed in COPF treatment as compared to non-prime control  and H control ,B.p < 0.001) increase in protein contents under saline conditions as compared to control plants. The maximum increase in protein content was recorded in both COP and COF treatments.An inverse relation of protein contents was observed with increasing salinity treatments. Maximum decrease in protein content was found at highest salinity (200 mM NaCl). However, coumarin-treated plants showed significant (p < 0.001) with increasing salinity treatments throughout the experiment. However, all COU treatments  further aided the antioxidant enzyme activities. The maximum enzymatic activities of CAT, APX, and GPX were observed at highest salinity in the COPF treatment as compared to control and other COU treatments  could be due to increase in osmotic, ionic, and oxidative stresses, which are reported to inhibit various physiological, morphological, and anatomical processes of plants . On the cia faba , rice  in Sorghum leaves. Similarly, a greater increase in Fv/Fm in COU-treated plants suggest more energy assimilation and conversion into ATP and NADPH, which are ultimately used for biomass production and defense systems of Sorghum under saline conditions  have generally strong antioxidant nature that can protect ROS-medicated injuries of cellular components and membranes, especially under stress  were also minimized by activating enzymatic and non-enzymatic antioxidant defense system. The combined application of primed and foliar spray (COPF) displayed better results than their individual ones. Therefore, COPF represents an efficient mode of COU application, which can be utilized for growth improvement and biomass production of a multipurpose crop Sorghum bicolor from saline degraded lands. However, the effect of COU on endogenous hormones and accurate estimation of their level of induction as well as the molecular modifications underlying COU biosynthesis needs to be evaluated in future studies.Our results indicated that exogenous application of COU significantly enhanced salinity resistance and increased the growth of The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.MA and MQ conceived the idea and helped in manuscript writing and proofreading. RS executed the idea and conducted the experiments. XW and AM provided technical expertise. RS, SF, and TH helped in data collection and analyses. All authors have read the manuscript, helped in revision, and approved the article.The publication of the present work is supported by the Natural Science Basic Research Program of Shaanxi Province (grant no. 2018JQ5218), the National Natural Science Foundation of China (51809224), and Top Young Talents of Shaanxi Special Support Program.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.


We investigated the association between albuminuria and hypertensive retinopathy (HR) in hypertensive adults.This was a cross-sectional subgroup analysis of data from the China Stroke Primary Prevention Trial. We enrolled 2,964 hypertensive adults in this study. Keith-Wagener-Barker stages was used to assess HR. The urinary albumin to creatinine ratio (UACR) was calculated to evaluate albuminuria.n = 2, 271) of the participants, albuminuria was found in 11.1% (n = 330). The UACR levels were significantly higher in subjects with HR than in those without HR . In the subgroup analyses, the association between HR and UACR was stronger in current smokers (p for interaction = 0.014). The correlation between HR grades 1 and 2 and UACR was stronger in subjects with higher triglyceride levels (≥ 1.7 mmol/L), but for grade 3 HR, this correlation was stronger in subjects with lower triglycerides levels . The odds of albuminuria were significantly higher in subjects with HR than in those without HR . In the subgroup analyses, the association between HR grades 1 and 2 and albuminuria was stronger in subjects with higher triglycerides levels (≥ 1.7 mmol/L), but for grade 3 HR, this correlation was stronger in subjects with lower triglyceride levels .HR was found in 76.6% (HR was positively correlated with albuminuria in hypertensive Chinese adults. This correlation was more remarkable when the population was stratified by triglycerides levels and smoking status. HR can be used as an indicator of early renal injury.The online version contains supplementary material available at 10.1186/s12886-023-02807-6. Approximately one-third of people in China suffer from hypertension . ChronicDipstick proteinuria tests are a common and inexpensive method for screening renal diseases, but they are not sufficiently precise . A totalRetinal blood vessels are similar in anatomy and physiology to vessels in other end organs. Retinal microvascular abnormalities (RMAs), especially vasoconstriction, stenosis and enhanced arterial reflex, are considered the main pathological features of hypertension and are closely related to the left ventricular failure, stroke, nephropathy, and cardiovascular disease observed in hypertensive patients . RetinalThe relationship between RMA and albuminuria has been reported in previous studies, but their results are controversial. For example, Bao et al. found that a lower retinal arteriovenous ratio was associated with higher albuminuria , but no The purpose of this study was to assess the correlation between albuminuria and hypertensive retinopathy (HR) in hypertensive adults in rural China. These data may provide a theoretical basis for the use of fundus examination to screen for early renal injury in hypertensive subjects.http://clinicaltrials.gov/, NCT number: NCT00794885.This is a cross-sectional study. Data used in this analysis were obtained from the China Stroke Primary Prevention Trial, a multicenter, double-blind and randomized clinical study performed in rural China. The purpose of the China Stroke Primary Prevention Trial was to compare the efficacy of folic acid combined with enalapril and enalapril alone in preventing stroke in Chinese hypertensive adults . The stu2 (m2).The general information related to the participants was collected through a questionnaire. Past history of illness, current medication use, smoking and drinking habits were recorded in detail. Smoking and drinking habits were each categorized into 3 levels: current smoking or drinking, former smoking or drinking and never smoking or drinking. Smoking at least 1 cigarette per day for 6 months was defined as current smoking. Drinking at least once a week for 6 months was defined as current drinking. The blood pressure of all participants was measured in the sitting position after at least 10 min of rest. The measurements were made 3 times at two-minute intervals, and the results were averaged. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg, diastolic blood pressure (DBP) ≥ 90 mmHg, or the use of antihypertensive drugs [All participants provided spot urine samples, and fasting venous blood was drawn. The samples were tested in the laboratory of the National Clinical Research Center for Kidney Disease, Nanfang Hospital, Guangzhou, China. The test methods were as follows. Triglyceride (TG), total cholesterol (TCHO), serum creatine (Scr), FBG, homocysteine (HCY) and uric acid (UA) levels were tested using automatic clinical analyzers (Beckman Coulter); Hyperuricemia was defined as UA ≥ 360 μmol/L in females and 420 μmol/L in males ; the estMacula-centered and nonmydriatic fundus pictures were taken by fundus cameras  and randomly assessed by 4 eye doctors in a double-masked manner. The assessment of the effect of hypertension on retinal vessels was based on the Keith-Wagener-Barker stages of HR , 13 (Sup2), treatment group , SBP (< 140 or ≥ 140 mmHg), TCHO (< 5.2 or ≥ 5.2 mmol/L), TG (< 1.7 or ≥ 1.7 mmol/L), FBG (< 7.0 or ≥ 7.0 mmol/L), HCY (< 10 or ≥ 10 and < 15 or ≥ 15 μmol/L), hyperuricemia (yes or no), and alcohol consumption and smoking status . Tests of interactions were performed to assess whether a variable influenced the effect of HR on UACR and albuminuria. The outcomes were expressed as the β or odds ratio (OR) with 95% confidence intervals (CIs). HR was transformed into continuous variables for the trend test. P < 0.05 was considered statistically significant.All statistical analyses were conducted using EmpowerStats  software and R (version 3.4.3). Among 3121 participants, only one female was diagnosed with grade 4 HR. Due to an insufficient sample size, subjects with grade 4 were not grouped for analysis. Then, according to the continuous distribution data of albuminuria, we selected the middle 95% of the population, and a total of 2964 subjects were included in the study  of the 2964 participants, including 58.9%  who were categorized as grade 1, 15.0% (n = 446) who were categorized as grade 2, and 2.6% (n = 78) who were categorized as grade 3.HR was found in 76.6% (n = 330). Compared with the normal subjects, the subjects with HR had a higher BMI (p = 0.035), SBP (p = 0.006), DBP (p = 0.002), UA (p = 0.005), Scr (p =  < 0.001) and UACR (p = 0.003), a lower eGFR (p = 0.007), and a higher proportion of individuals with diabetes (p = 0.045) and albuminuria (p = 0.004).The baseline characteristics of the subjects are shown in Table p = 0.042; grade 2, β = 2.69, 95% CI: 0.69, 4.68, p = 0.008; grade 3, β = 5.61, 95% CI: 1.69, 9.54, p = 0.005). After adjusting for age, sex and BMI, this trend was sustained . After adjusting for age, sex, MTHFR C677T genotypes, BMI, SBP, DBP, FBG, TG, TCHO, eGFR, folate, HCY, smoking status, alcohol consumption, and the use of antihypertensive medicine, the trend was also sustained .The results of multivariable regression analyses between HR and UACR are shown in Table p = 0.011; grade 2, OR = 1.87, 95% CI: 1.28, 2.75, p = 0.001; grade 3, OR = 2.32, 95% CI: 1.20, 4.47, p = 0.012). This trend was sustained after adjusting for variables in model I  and after adjusting for variables in model II .The results of multivariable regression analyses between HR and albuminuria are shown in Table p for interaction = 0.023) and smoking status (p for interaction = 0.014). The correlation between UACR and HR was stronger in current smokers . There were strong correlations between UACR and HR grades 1 and 2 in subjects with TGs ≥ 1.7 mmol/L . However, in regard to grade 3, a strong correlation between UACR and HR was found in subjects with TG < 1.7 mmol/L .The results of stratified analyses between HR and the UACR are shown in Table p for interaction = 0.014). There was a strong correlation between albuminuria and HR grades 1 and 2 in subjects with TGs ≥ 1.7 mmol/L . However, in regard to grade 3, a strong correlation between albuminuria and HR was found in subjects with TG < 1.7 mmol/L .The results of stratified analyses between HR and albuminuria are shown in Table The prevalence of albuminuria and CKD was 9.4% and 10.8%, respectively in the general Chinese population . Since hRetinopathy and nephropathy are both microvascular diseases and target organ damage observed in hypertension, and there is a definite correlation between them. CKD has been associated with various ocular diseases, such as cataracts, glaucoma, diabetic retinopathy, age-related macular degeneration and vision loss due to various causes . In Bao’In this study, there was a significant correlation between HR grade and albuminuria in hypertensive subjects. In subjects with grade 1 HR, compared with the normal subjects, the UACR increased by 1.42 mg/g, and the odds of albuminuria increased by 57%; in subjects with grade 2 HR, the UACR increased by 2.62 mg/g, and the odds of albuminuria increased by 102%; and in subjects with grade 3 HR, the UACR increased by 5.17 mg/g, and the odds of albuminuria increased by 112%. This suggests that with the aggravation of HR, albuminuria is more obvious, and renal damage is more serious. As a systemic disease, the effects of hypertension on the retinal microvascular and renal microvascular are often parallel . When thHowever, contradictory findings have also been reported. For example, in Bao’s study, the central retinal artery equivalent, central retinal vein equivalent and arteriovenous ratio were not associated with albuminuria and reduced renal function in hypertensive patients , and MasIn the stratified analyses, a stronger correlation between the UACR and HR was found in current smokers and subjects with higher TG levels, except for in those with grade 3 HR, and the correlations between UACR and grade 3 HR were stronger in subjects with lower TG levels.Smoking can induce inflammation, oxidative stress and renal fibrosis, leading to kidney injury . SimilarThe strength of this study is that we found a positive correlation between HR and albuminuria in hypertensive adults in rural China. We evaluated the possible effect modifiers in detail and found that this correlation was stronger when the population was stratified by TG levels and smoking status. This finding provides evidence for exploring the relationship between smoking, TG and RMA in the future. It also provides a theoretical basis for focusing on screening and follow-up in people with a possibility of kidney damage, such as smokers with HR. Retinal blood vessels, the only blood vessels that can be directly observed in vivo, are an important marker of systemic vascular disease. If ophthalmologists better understand the relationship between fundus diseases and systemic diseases, they will be able to detect many potential systemic diseases earlier. In the CSPPT cohort, we have been continuously following up the patients for many years to collect more endpoint data for exploration and analysis. We hope to obtain more meaningful information about the correlation between HR and other microvascular diseases by studying this cohort.There are several limitations to this study. First, because of the limitations of cross-sectional studies, causality could not be obtained. Second, since the fundus pictures were obtained by a nonmydriatic fundus camera, peripheral lesions may have been missed. HR often occurs around the optic disc and macula, and nonmydriatic fundus examination can obtain most of the information. Third, we evaluated RMA based on the Keith-Wagener-Barker stage instead of quantitative parameters. This evaluation of clinical signs may lack objectivity, especially in evaluating “generalized retinal arteriolar narrowing” in grade 1 HR and “definite focal narrowing” in grade 2 HR. To improve the consistency, we trained the evaluators in detail before the study and conducted a consistency test . In addiIn conclusion, we found that HR was positively correlated with albuminuria in hypertensive adults. This correlation was stronger in current smokers. The correlation between HR grades 1 and 2 and albuminuria was stronger in subjects with higher TG levels, but in regard to grade 3 HR, this correlation was stronger in subjects with lower TG levels. RMA associated with hypertension can be used as an indicator of early renal injury. These results highlight the need for albuminuria screening in hypertensive patients complicated with HR to ensure early detection of CKD.Additional file 1: Supplementary Table 1. The Keith-Wagener-Barker classification for hypertensive retinopathy.