Congenital Risk Factors for Chronic Kidney Disease in Patients With Persistent Cloaca: Results From a Nationwide Survey in Japan.

BACKGROUND: We conducted a nationwide survey of persistent cloaca (PC) to investigate the renal function outcomes and factors affecting chronic kidney disease (CKD) in patients with PC. METHOD: Information from 466 patients with PC was obtained via a questionnaire in this study. The 290 patients (62.2%) with renal function data were classified into 2 groups based on their estimated glomerular filtration rate: advanced CKD group (<30 mL/min/1.73 m2 [or post-renal replacement therapy]) and non-advanced CKD group (≥30 mL/min/1.73 m2). Univariate and multivariate analyses were performed to identify risk factors for CKD that may affect the renal function, including renal and urinary tract malformations, associated anomalies, and urinary tract treatment. The advanced CKD group was divided into two groups based on age to evaluate age-related differences (younger- and older-age CKD groups). RESULTS: A regression analysis revealed that congenital renal malformations (odds ratio [OR]: 14.06, 95% confidence interval [CI]:3.07-131.65, p < 0.0001), urinary tract obstruction (OR:4.28, 95%CI:1.12-24.23, p < 0.05), and sacral agenesis (OR:4.54, 95% CI:0.84-30.67, p < 0.05) were significantly associated with advanced CKD. In the univariate analysis of factors affecting the renal prognosis, clean intermittent catheterization (CIC) (OR:4.18, 95%CI:1.21-16.45, p = 0.015), vesicostomy (OR:3.65, 95%CI:1.11-12.98, p = 0.019), and surgery for vesicoureteral reflux (OR:5.43, 95%CI:1.41-22.73, p = 0.006) were significantly associated with advanced CKD. Based on the univariate analysis, hydrometrocolpos was significantly more prevalent in the older-age CKD group compared to the younger-age CKD group (p < 0.05). CONCLUSION: CKD development in patients with PC is influenced by a complex interplay of factors, including renal malformations and neurogenic bladder dysfunction due to spinal anomalies. LEVEL OF EVIDENCE: III (Study of Diagnostic Test, Study of nonconsecutive patients, and/or without a universally applied "gold" standard).

Vaccine Therapy for Heart Failure Targeting the Inflammatory Cytokine Igfbp7.

BACKGROUND: The heart comprises many types of cells such as cardiomyocytes, endothelial cells (ECs), fibroblasts, smooth muscle cells, pericytes, and blood cells. Every cell type responds to various stressors (eg, hemodynamic overload and ischemia) and changes its properties and interrelationships among cells. To date, heart failure research has focused mainly on cardiomyocytes; however, other types of cells and their cell-to-cell interactions might also be important in the pathogenesis of heart failure. METHODS: Pressure overload was imposed on mice by transverse aortic constriction and the vascular structure of the heart was examined using a tissue transparency technique. Functional and molecular analyses including single-cell RNA sequencing were performed on the hearts of wild-type mice and EC-specific gene knockout mice. Metabolites in heart tissue were measured by capillary electrophoresis-time of flight-mass spectrometry system. The vaccine was prepared by conjugating the synthesized epitope peptides with keyhole limpet hemocyanin and administered to mice with aluminum hydroxide as an adjuvant. Tissue samples from heart failure patients were used for single-nucleus RNA sequencing to examine gene expression in ECs and perform pathway analysis in cardiomyocytes. RESULTS: Pressure overload induced the development of intricately entwined blood vessels in murine hearts, leading to the accumulation of replication stress and DNA damage in cardiac ECs. Inhibition of cell proliferation by a cyclin-dependent kinase inhibitor reduced DNA damage in ECs and ameliorated transverse aortic constriction-induced cardiac dysfunction. Single-cell RNA sequencing analysis revealed upregulation of Igfbp7 (insulin-like growth factor-binding protein 7) expression in the senescent ECs and downregulation of insulin signaling and oxidative phosphorylation in cardiomyocytes of murine and human failing hearts. Overexpression of Igfbp7 in the murine heart using AAV9 (adeno-associated virus serotype 9) exacerbated cardiac dysfunction, while EC-specific deletion of Igfbp7 and the vaccine targeting Igfbp7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes under pressure overload. CONCLUSIONS: Igfbp7 produced by senescent ECs causes cardiac dysfunction and vaccine therapy targeting Igfbp7 may be useful to prevent the development of heart failure.

Comprehensive metabolic modulations of sphingolipids are promising severity indicators in COVID-19.

The COVID-19 pandemic, caused by SARS-CoV-2, has had a significant worldwide impact, affecting millions of people. COVID-19 is characterized by a heterogenous clinical phenotype, potentially involving hyperinflammation and prolonged tissue damage, although the exact underlying mechanisms are yet to be fully understood. Sphingolipid metabolites, which govern cell survival and proliferation, have emerged as key players in inflammatory signaling and cytokine responses. Given the complex metabolic pathway of sphingolipids, this study aimed to understand their potential role in the pathogenesis of COVID-19. We conducted a comprehensive examination of sphingolipid modulations across groups classified based on disease severity, incorporating a time-course in serum and urine samples. Several sphingolipids, including sphingosine, lactosylceramide, and hexosylceramide, emerged as promising indicators of COVID-19 severity, as validated by correlation analyses conducted on both serum and urine samples. Other sphingolipids, such as sphingosine 1-phosphate, ceramides, and deoxy-dihydroceramides, decreased in both COVID-19 patients and individuals with non-COVID infectious diseases. This suggests that these sphingolipids are not specifically associated with COVID-19 but rather with pathological conditions caused by infectious diseases. Our analysis of urine samples revealed elevated levels of various sphingolipids, with changes dependent on disease severity, potentially highlighting the acute kidney injury associated with COVID-19. This study illuminates the intricate relationship between disturbed sphingolipid metabolism, COVID-19 severity, and clinical factors. These findings provide valuable insights into the broader landscape of inflammatory diseases.

The postoperative renal function of persistent cloaca patients treated by posterior sagittal anorecto-urethro-vaginopalsty: results of a nationwide survey in Japan.

PURPOSE: We investigated the postoperative renal function in persistent cloaca (PC) patients who underwent posterior sagittal anorecto-urethro-vaginopalsty (PSARUVP) and factors influencing the renal functional outcomes. METHODS: A questionnaire survey was distributed to 244 university and children's hospitals across Japan. Of the 169 patients underwent PSARUVP, 103 patients were enrolled in the present study. Exclusion criteria was patients without data of renal prognosis. RESULTS: The present study showed that renal anomalies (p = 0.09), vesicoureteral reflux (VUR) (p = 0.01), and hydrocolpos (p = 0.07) were potential factors influencing a decline in the renal function. Approximately half of the patients had a normal kidney function, but 45.6% had a reduced renal function (Stage ≥ 2 chronic kidney disease: CKD). The incidence of VUR was significantly higher in the renal function decline (RFD) group than those in the preservation (RFP) group (p = 0.01). Vesicostomy was significantly more frequent in the RFD group than in the RFP group (p = 0.04). Urinary tract infections (p < 0.01) and bladder dysfunction (p = 0.04) were significantly more common in patients with VUR than in patients without VUR. There was no association between the VUR status and the bowel function. CONCLUSIONS: Prompt assessment and treatment of VUR along with bladder management may minimize the decline in the renal function.

Alzheimer's disease manifests abnormal sphingolipid metabolism.

Introduction: Alzheimer's disease (AD) is associated with disturbed metabolism, prompting investigations into specific metabolic pathways that may contribute to its pathogenesis and pathology. Sphingolipids have garnered attention due to their known physiological impact on various diseases. Methods: We conducted comprehensive profiling of sphingolipids to understand their possible role in AD. Sphingolipid levels were measured in AD brains, Cerad score B brains, and controls, as well as in induced pluripotent stem (iPS) cells (AD, PS, and control), using liquid chromatography mass spectrometry. Results: AD brains exhibited higher levels of sphingosine (Sph), total ceramide 1-phosphate (Cer1P), and total ceramide (Cer) compared to control and Cerad-B brains. Deoxy-ceramide (Deoxy-Cer) was elevated in Cerad-B and AD brains compared to controls, with increased sphingomyelin (SM) levels exclusively in Cerad-B brains. Analysis of cell lysates revealed elevated dihydroceramide (dhSph), total Cer1P, and total SM in AD and PS cells versus controls. Multivariate analysis highlighted the relevance of Sph, Cer, Cer1P, and SM in AD pathology. Machine learning identified Sph, Cer, and Cer1P as key contributors to AD. Discussion: Our findings suggest the potential importance of Sph, Cer1P, Cer, and SM in the context of AD pathology. This underscores the significance of sphingolipid metabolism in understanding and potentially targeting mechanisms underlying AD.

Development of an advanced liquid chromatography-tandem mass spectrometry measurement system for simultaneous sphingolipid analysis.

Mass spectrometry-based lipidomics approaches offer valuable tools for the detection and quantification of various lipid species, including sphingolipids. The present study aimed to develop a new method to simultaneously detect various sphingolipid species that applies to diverse biological samples. We developed and validated a measurement system by employing a single-column liquid chromatography-mass spectrometry system utilizing a normal-phase separation mode with positive ionization. The measurement system provided precision with a coefficient of variant below 20% for sphingolipids in all types of samples, and we observed good linearity in diluted serum samples. This system can measure the following sphingolipids: sphingosine 1-phosphate (S1P), sphingosine (Sph), dihydroS1P (dhS1P), dihydroSph (dhSph), ceramide 1-phosphate (Cer1P), hexosylceramide (HexCer), lactosylceramide (LacCer), dh-ceramide, deoxy-ceramide, deoxy-dh-ceramide, and sphingomyelin (SM). By measuring these sphingolipids in cell lysates where S1P lyase expression level was modulated, we could observe significant and dynamic modulations of sphingolipids in a comprehensive manner. Our newly established and validated measurement system can simultaneously measure many kinds of sphingolipids in biological samples. It holds great promise as a valuable tool for laboratory testing applications to detect overall modulations of sphingolipids, which have been proposed to be involved in pathogenesis processes in a series of elegant basic research studies.

Myocardial DNA Damage Predicts Heart Failure Outcome in Various Underlying Diseases.

BACKGROUND: Reliable predictors of treatment efficacy in heart failure have been long awaited. DNA damage has been implicated as a cause of heart failure. OBJECTIVES: The purpose of this study was to investigate the association of DNA damage in myocardial tissue with treatment response and prognosis of heart failure. METHODS: The authors performed immunostaining of DNA damage markers poly(ADP-ribose) (PAR) and γ-H2A.X in endomyocardial biopsy specimens from 175 patients with heart failure with reduced ejection fraction (HFrEF) of various underlying etiologies. They calculated the percentage of nuclei positive for each DNA damage marker (%PAR and %γ-H2A.X). The primary outcome was left ventricular reverse remodeling (LVRR) at 1 year, and the secondary outcome was a composite of cardiovascular death, heart transplantation, and ventricular assist device implantation. RESULTS: Patients who did not achieve LVRR after the optimization of medical therapies presented with significantly higher %PAR and %γ-H2A.X. The ROC analysis demonstrated good performance of both %PAR and %γ-H2A.X for predicting LVRR (AUCs: 0.867 and 0.855, respectively). There was a negative correlation between the mean proportion of DNA damage marker-positive nuclei and the probability of LVRR across different underlying diseases. In addition, patients with higher %PAR or %γ-H2A.X had more long-term clinical events (PAR HR: 1.63 [95% CI: 1.31-2.01]; P < 0.001; γ-H2A.X HR: 1.48 [95% CI: 1.27-1.72]; P < 0.001). CONCLUSIONS: DNA damage determines the consequences of human heart failure. Assessment of DNA damage is useful to predict treatment efficacy and prognosis of heart failure patients with various underlying etiologies.

Diagnostic accuracy of diastolic pressure ratio using a pressure microcatheter for intracoronary physiological assessment.

Recently, instantaneous wave-free ratio (iFR) has emerged as an alternative to the fractional flow reserve (FFR) for intracoronary physiological assessment. Although all diastolic resting indices are reportedly identical to the iFR, limited data exist on diastolic pressure ratio (dPR) measured using a microcatheter (dPRmicro). This study aimed to evaluate the diagnostic accuracy of dPRmicro compared to FFR measured using a microcatheter (FFRmicro) in real-world practice for intracoronary physiological assessment. This was a single-center, retrospective, observational study. We identified 103 consecutive suspected angina pectoris patients (107 lesions) who underwent dPRmicro and FFRmicro measurement using the Navvus® catheter at Takasaki Heart Hospital from March 2019 to June 2019. A total of 103 lesions in 103 patients were finally included in the study. The mean FFRmicro and dPRmicro values were 0.80 and 0.88, respectively. With an FFRmicro ≤ 0.80, the dPRmicro showed a diagnostic accuracy of 79.6%, sensitivity of 74.6%, specificity of 87.5%, positive predictive value of 90.4%, and negative predictive value of 68.6%. The area under the receiver operating characteristic (ROC) curve was 0.894 (95% confidence interval, 0.833-0.956), and the optimal cut-off value for dPRmicro derived from the ROC analysis was 0.90. dPRmicro and FFRmicro values were discordant in 21/103 cases (20.4%). As a multivariable logistic regression analysis was performed, the male sex (vs. female) had a statistically significant association with a dPRmicro-FFRmicro discordance (OR 4.91; 95% CI, 1.04-23.0; P = 0.044). No other factors were found to be significantly associated with the discordance. In conclusion, dPRmicro measured using a microcatheter had good diagnostic accuracy and correlation with FFRmicro, hence, it can be useful for making revascularization decisions. However, re-studies in larger populations will be needed to better understand the properties of diastolic resting index measured using a microcatheter in clinical settings.

The clinical features of patients who underwent bladder augmentation of cloacal exstrophy and their functional outcomes: the results of a nationwide survey in Japan.

PURPOSE: Cloacal exstrophy (CE) patients may need bladder reconstruction after initially undergoing surgery to obtain continence and improve their quality of life. This study attempts to clarify the clinical features of CE patients who underwent bladder augmentation (BA) and their urinary functional outcomes based on a nationwide survey in Japan. METHODS: A questionnaire survey was conducted, and 150 CE patients were enrolled. Their clinical characteristics and urinary outcomes were reviewed. RESULTS: BA was performed in 52 patients (34.7%). Most cases underwent early bladder closure at initial surgery in neonate period. The age at the BA was performed 6.4 [6-9.0] years. Among them, the most used organ for BA was ileum (n = 30, 57.7%). Regarding the outcomes, the age when the renal function was evaluated was 14.0 [10.0-20.5] years and the serum creatinine level was 0.44 [0.36-0.60] (mg/dl). Clean intermittent catheterization was required in 37 (71.2%) patients. On the other hand, no dialysis or kidney transplantation was necessary in any of these patients. CONCLUSION: The renal function and conditions of patients who underwent BA were relatively well preserved. Individualized management with a stepwise surgical approach for CE patients should thus be considered in the future.

Posterior sagittal anorecto-urethro-vagino-plasty in the late period was associated with the long-term bowel function in patients with persistent cloaca: results of a nationwide survey in Japan.

PURPOSE: After conducting a nationwide survey of persistent cloaca (PC), we assessed whether or not the timing of definitive anorectoplasty affects the long-term bowel function of patients with PC. METHODS: Patient information was obtained via questionnaire, and a total of 169 PC patients who underwent posterior sagittal anorectourethrovaginoplasty (PSARUVP) were enrolled in this study. Patients were classified into 2 groups based on their operative period, which was analyzed by the area under the receiver operating characteristic curve: the early group (EG) underwent anorectoplasty at ≤ 18 months old (n = 106), and the late group (LG) underwent anorectoplasty at > 18 months old (n = 63). The bowel function was evaluated using the evacuation score of the Japan Society of Anorectal Malformation Study Group. We also examined the postoperative results of vaginoplasty. RESULTS: The total evacuation score was significantly higher in the EG than in the LG (5.2 ± 1.7 vs. 4.2 ± 1.8, p = 0.003). The frequency of bowel movement and the constipation scores were significantly higher in the EG than in the LG (1.4 ± 0.6 vs. 1.2 ± 0.7, p < 0.05, 2.4 ± 1.0 vs. 2.1 ± 1.0, p < 0.05, respectively). Postoperative vaginal stenosis was observed in 18 cases (10.7%), of which 16 could be reconstructed transperineally. CONCLUSION: PSARUVP should be performed in early infancy and facilitate vaginal reconstruction.

TEAD1 trapping by the Q353R-Lamin A/C causes dilated cardiomyopathy.

Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEA domain transcription factor 1 (TEAD1) by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R-LMNA-related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in LMNA mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from patients with DCM with the LMNA mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of LMNA-related DCM.

Clinical features of patients who underwent anoplasty for cloacal exstrophy and their functional outcomes: the results of a nationwide survey in Japan.

PURPOSE: This study was performed to clarify the clinical features of cloacal exstrophy (CE) patients who underwent anoplasty and their functional outcomes based on a nationwide survey in Japan. METHODS: A questionnaire survey was conducted and data were obtained from 229 CE patients. After the exclusion of non-surviving patients and unknown data, 195 patients were enrolled. We compared the patient characteristics of the no anoplasty group (NAP group) to the anoplasty group (AP group). The defecation function of patients who underwent anoplasty was evaluated. RESULTS: The AP group had significantly lower rates of omphalocele (p = 0.045) and spinal defects (p = 0.003) than the NAP group. Of the 195 patients enrolled in this study, only 17 (8.7%) underwent anoplasty. Of the 17 patients who underwent anoplasty, 7 (41.1%) eventually had a permanent stoma after anoplasty [after ileostomy: n = 3 (60.0%), after colostomy: n = 4 (44.4%)]. Regarding soiling, 4 patients (66.7%) showed the absence of soiling, 2 (33.3%) showed accidental soiling, and no patients showed frequent soiling. CONCLUSION: In our study, spinal defects may have affected the determination of anoplasty. Anoplasty may improve the quality of life, because defecation can be kept clean, but indications, including colon function, may be carefully considered.

Nitrogen fixation and nifH gene diversity in cyanobacteria living on feather mosses in a subalpine forest of Mt. Fuji.

In the boreal forests, feather mosses such as Hylocomium splendens and Pleurozium schreberi are colonized by cyanobacteria, which provide large amounts of nitrogen to forest ecosystems through nitrogen fixation. Although these feather mosses are also ubiquitous in subalpine forests of East Asia, little is known regarding their associated cyanobacteria and their ability to fix nitrogen. In this study, we investigated (1) whether cyanobacteria co-exist and fix nitrogen in the two species of feather mosses that cover the ground surface in a subalpine forest of Mt. Fuji, (2) whether cyanobacteria belonging to a common cluster with boreal forests are found in feather mosses in Mt. Fuji, and (3) whether moss-associated nitrogen fixation rates differed among moss growing substrates, canopy openness, and moss nitrogen concentrations in the same forest area. Our results showed that cyanobacteria colonized feather mosses in the subalpine forests of Mt. Fuji and acetylene reduction rates as an index of nitrogen fixation tended to be higher in H. splendens than in P. schreberi. Based on analysis of the nifH gene, 43 bacterial operational taxonomic units (OTUs) were identified, 28 of which represented cyanobacteria. Among the five clusters of cyanobacteria classified based on their nifH gene and identified in northern Europe, four (Nostoc cluster I, Nostoc cluster II, Stigonema cluster, and nifH2 cluster) were also found at Mt. Fuji. The acetylene reduction rate differed depending on the moss growing substrate and the total nitrogen concentration of moss shoots, and a strong negative correlation was observed with the total nitrogen concentration.

Cross-ancestry genome-wide analysis of atrial fibrillation unveils disease biology and enables cardioembolic risk prediction.

Atrial fibrillation (AF) is a common cardiac arrhythmia resulting in increased risk of stroke. Despite highly heritable etiology, our understanding of the genetic architecture of AF remains incomplete. Here we performed a genome-wide association study in the Japanese population comprising 9,826 cases among 150,272 individuals and identified East Asian-specific rare variants associated with AF. A cross-ancestry meta-analysis of >1 million individuals, including 77,690 cases, identified 35 new susceptibility loci. Transcriptome-wide association analysis identified IL6R as a putative causal gene, suggesting the involvement of immune responses. Integrative analysis with ChIP-seq data and functional assessment using human induced pluripotent stem cell-derived cardiomyocytes demonstrated ERRg as having a key role in the transcriptional regulation of AF-associated genes. A polygenic risk score derived from the cross-ancestry meta-analysis predicted increased risks of cardiovascular and stroke mortalities and segregated individuals with cardioembolic stroke in undiagnosed AF patients. Our results provide new biological and clinical insights into AF genetics and suggest their potential for clinical applications.

Analysis of the potential risk factors for defecation problems and their bowel management based on the long-term bowel function in patients with persistent cloaca: results of a nationwide survey in Japan.

AIM OF THE STUDY: We conducted a nationwide survey of persistent cloaca (PC) to determine its current status in Japan. This study clarifies the potential risk factors for defecation problems in patients with PC. METHODS: Patient information was obtained via questionnaire, and a total of 213 PC patients who responded to a questionnaire on defecation problems and their bowel functions were enrolled in this study. We evaluated the constipation, incontinence, and soiling as bowel functions. Univariate and multivariate analyses were performed using a logistic regression analysis to clarify the risk factors for defecation problems. RESULTS: Of 213 patients with PC, 55 (25.8%) had defecation problems. A multivariate logistic regression analysis showed that sacral agenesis, as an associated anomaly, was significantly associated with defecation problems (odds ratio [OR] 3.19, 95% confidence interval [CI] 1.11-9.16, p = 0.03). The other multivariate logistic regression analysis showed that the PC patients who underwent antegrade continence enema and regularly took laxatives after anorectoplasty had defecation problems (OR 12.4, 95% CI 2.35-65.6, p = 0.003, OR 2.84, 95% CI 1.24-6.55, p = 0.01). CONCLUSION: Sacral agenesis is the potential risk factor of defecation problems in the patients with PC who underwent anorectoplasty. Those patients require vigorous defecation management.

Clinical features of Mayer-Rokitansky-Küster-Haüser syndrome diagnosed at under 16 years old: results from a questionnaire survey conducted on all institutions of pediatric surgery and pediatric urology in Japan.

PURPOSE: Mayer-Rokitansky-Küster-Häuser syndrome (MRKH) usually presents with primary amenorrhea after puberty. The present study clarified the clinical features of MRKH diagnosed at under 16 years old. METHODS: We conducted a questionnaire survey to determine the status of MRKH in Japan. Twenty-one MRKH patients were enrolled, and the patient background and clinical features were analyzed. RESULTS: The median age at the diagnosis was 2.6 [1.0-9.0] years. Three patients (14.3%) were diagnosed with type I MRKH, while 18 (85.7%) were diagnosed with type II. The associated anomalies included (some cases overlapped): anorectal malformation (ARM) (n = 13, 72.2%), renal malformation (n = 12, 66.7%), vertebral malformation (n = 11, 61.1%), esophageal atresia (n = 5, 27.8%), and cardiac malformation (n = 4, 22.2%). The comparison of patients with and without ARM revealed that patients with ARM were significantly younger than those without ARM at the time of the diagnosis (1.5 [1-2.6] years vs. 9.1 [8.2-11.7] years, p < 0.05). Associated ARM was the most frequent reason for the diagnosis of MRKH (n = 10, 47.6%). CONCLUSIONS: MRKH patients with some associated anomalies, especially ARM, were frequently diagnosed in preoperative imaging examinations or radical operation for ARM. Pediatric surgeons should pay close attention to female patients with ARM to prevent errors in the diagnosis of MRKH.

Risk factor analysis of irreversible renal dysfunction based on fetal ultrasonographic findings in patients with persistent cloaca: Results from a nationwide survey in Japan.

AIM OF THE STUDY: We conducted a nationwide survey of persistent cloaca (PC) to determine its current status in Japan. We focused on the relationship between fetal ultrasonographic findings and irreversible renal dysfunction in PC. METHOD: Patient information was obtained via questionnaire, and 466 PC patients were ultimately enrolled in this study. Fifteen patients (3.2%) who required dialysis or kidney transplantation were compared to those who were able to survive with their native kidney. Univariable and multivariable analyses were performed using a logistic regression analysis to clarify the relationship between irreversible renal dysfunction and fetal ultrasonographic findings. RESULTS: A multivariable logistic analysis showed that fetal ultrasonic findings of oligohydramnios independently increased the risk of irreversible renal dysfunction (adjusted odds ratio [OR] 5.8, 95% confidence interval [CI] 1.7-20, p = 0.005). A regression analysis showed that fetal ultrasonographic findings of hydroureteronephrosis (crude OR 5.6, 95% CI 0.9-24, p = 0.03) tended to be associated with irreversible renal dysfunction. In the PC patients with oligohydramnios, however, the ultrasonographic findings and associated anomalies did not affect the renal prognosis. The 15 renal dysfunction patients were treated as follows: hemodialysis (n = 4), peritoneal dialysis (n = 3), living donor renal transplantation (n = 8), and cadaveric renal transplantation (n = 1). CONCLUSION: Fetal ultrasonographic findings of oligohydramnios increase the risk of irreversible renal dysfunction. Such findings suggest we consider the need for earlier therapeutic intervention, such as fetal and postnatal treatment, to prevent the progression of renal dysfunction. LEVEL OF EVIDENCE: III (Study of diagnostic test, study of nonconsecutive patients and/or without a universally applied "gold" standard).

Spatiotemporal transcriptome analysis reveals critical roles for mechano-sensing genes at the border zone in remodeling after myocardial infarction.

The underlying mechanisms of ventricular remodeling after myocardial infarction (MI) remain largely unknown. In this study, we performed an integrative analysis of spatial transcriptomics and single-nucleus RNA sequencing (snRNA-seq) in a murine MI model and found that mechanical stress-response genes are expressed at the border zone and play a critical role in left ventricular remodeling after MI. An integrative analysis of snRNA-seq and spatial transcriptome of the heart tissue after MI identified the unique cluster that appeared at the border zone in an early stage, highly expressing mechano-sensing genes, such as Csrp3. AAV9-mediated gene silencing and overexpression of Csrp3 demonstrated that upregulation of Csrp3 plays critical roles in preventing cardiac remodeling after MI by regulation of genes associated with mechano-sensing. Overall, our study not only provides an insight into spatiotemporal molecular changes after MI but also highlights that the mechano-sensing genes at the border zone act as adaptive regulators of left ventricular remodeling.