Quinic acid regulated TMA/TMAO-related lipid metabolism and vascular endothelial function through gut microbiota to inhibit atherosclerotic.

BACKGROUND: Quinic acid (QA) and its derivatives have good lipid-lowering and hepatoprotective functions, but their role in atherosclerosis remains unknown. This study attempted to investigate the mechanism of QA on atherogenesis in Apoe-/- mice induced by HFD. METHODS: HE staining and oil red O staining were used to observe the pathology. The PCSK9, Mac-3 and SM22a expressions were detected by IHC. Cholesterol, HMGB1, TIMP-1 and CXCL13 levels were measured by biochemical and ELISA. Lipid metabolism and the HMGB1-SREBP2-SR-BI pathway were detected by PCR and WB. 16 S and metabolomics were used to detect gut microbiota and serum metabolites. RESULTS: QA or low-frequency ABX inhibited weight gain and aortic tissue atherogenesis in HFD-induced Apoe-/- mice. QA inhibited the increase of cholesterol, TMA, TMAO, CXCL13, TIMP-1 and HMGB1 levels in peripheral blood of Apoe-/- mice induced by HFD. Meanwhile, QA or low-frequency ABX treatment inhibited the expression of CAV-1, ABCA1, Mac-3 and SM22α, and promoted the expression of SREBP-1 and LXR in the vascular tissues of HFD-induced Apoe-/- mice. QA reduced Streptococcus_danieliae abundance, and promoted Lactobacillus_intestinalis and Ileibacterium_valens abundance in HFD-induced Apoe-/- mice. QA altered serum galactose metabolism, promoted SREBP-2 and LDLR, inhibited IDOL, FMO3 and PCSK9 expression in liver of HFD-induced Apoe-/- mice. The combined treatment of QA and low-frequency ABX regulated microbe-related Glycoursodeoxycholic acid and GLYCOCHENODEOXYCHOLATE metabolism in HFD-induced Apoe-/- mice. QA inhibited TMAO or LDL-induced HCAECs damage and HMGB1/SREBP2 axis dysfunction, which was reversed by HMGB1 overexpression. CONCLUSIONS: QA regulated the gut-liver lipid metabolism and chronic vascular inflammation of TMA/TMAO through gut microbiota to inhibit the atherogenesis in Apoe-/- mice, and the mechanism may be related to the HMGB1/SREBP2 pathway.

Use of phosphodiesterase 5 inhibitors is not associated with ocular adverse events.

BACKGROUND: Phosphodiesterase 5 inhibitor (PDE5i) use has been linked to a number of ocular side effects, such as serous retinal detachment (SRD), retinal vascular occlusion (RVO), and ischemic optic neuropathy (ION). AIM: We investigated the risk for SRD, RVO, and ION in patients using PDE5is. METHODS: We utilized the IBM MarketScan (2007-2021) Commercial and Medicare Supplemental Databases (version 2.0) for this analysis. To estimate overall events risk, Cox proportional hazard models were applied to calculate the hazard ratios (HRs) for erectile dysfunction (ED) diagnosis and the different treatments, adjusting for region, median age, obesity, diabetes mellitus, hyperlipidemia, smoking, hypertension, coronary artery disease, and sleep apnea. Additionally, the same analyses were performed to calculate the HRs for benign prostatic hyperplasia (BPH) diagnosis and the different treatments. OUTCOMES: HRs for SRD, RVO, and ION. RESULTS: In total, 1 938 262 men with an ED diagnosis were observed during the study period. Among them, 615 838 (31.8%) were treated with PDE5is. In total, 2 175 439 men with a BPH diagnosis were observed during the study period. Among them, 175 725 (8.1%) were treated with PDE5is. On adjusted Cox regression analysis, PDE5i use was not associated with SRD, RVO, ION, and any ocular event when compared with ED diagnosis and other ED treatments. Importantly, as the intensity of ED treatment increased, so did the risk of ocular events. In addition, PDE5i use was not associated with SRD and ION when compared with BPH diagnosis and other BPH treatments. In contrast, in patients with BPH, PDE5i use was associated with RVO (HR, 1.14; 95% CI, 1.06-1.23). Importantly, patients with BPH receiving other medical treatment (ie, 5a reductase/alpha blocker; HR, 1.11; 95% CI, 1.06-1.16) or surgical treatment (HR, 1.10; 95% CI, 1.02-1.19) had a higher risk of RVO. CLINICAL IMPLICATIONS: We did not observe any consistent association between PDE5i use and any ocular adverse events (SRD, RVO, and ION). STRENGTHS AND LIMITATIONS: Because we did not have access to the patients' medical records, we recorded outcome definitions using ICD-9 and ICD-10 coding. CONCLUSIONS: Patients using PDE5is for ED or BPH indications did not have an increased risk of ocular events, even when compared with other treatments for ED or BPH.

Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1.

Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.

Postoperative complications and pelvic organ prolapse recurrence following combined pelvic organ prolapse and rectal prolapse surgery compared with pelvic organ prolapse only surgery.

BACKGROUND: There is a growing interest in combined pelvic organ prolapse and rectal prolapse surgery for concomitant pelvic floor prolapse despite a paucity of data regarding complications and clinical outcomes of combined repair. OBJECTIVE: The primary objective of this study was to compare the <30-day postoperative complication rate in women undergoing combined POP + RP surgery with that of women undergoing pelvic organ prolapse-only surgery. The secondary objectives were to describe the <30-day postoperative complications, compare the pelvic organ prolapse recurrence between the 2 groups, and determine the preoperative predictors of <30-day postoperative complications and predictors of pelvic organ prolapse recurrence. STUDY DESIGN: This was a multicenter, retrospective cohort study at 5 academic hospitals. Patients undergoing combined pelvic organ prolapse and rectal prolapse surgery were matched by age, pelvic organ prolapse stage by leading compartment, and pelvic organ prolapse procedure compared with those undergoing pelvic organ prolapse-only surgery from March 2003 to March 2020. The primary outcome measure was <30-day complications separated into Clavien-Dindo classes. The secondary outcome measures were (1) subsequent pelvic organ prolapse surgeries and (2) pelvic organ prolapse recurrence, defined as patients who complained of vaginal bulge symptoms postoperatively. RESULTS: Overall, 204 women underwent combined surgery for pelvic organ prolapse and rectal prolapse, and 204 women underwent surgery for pelvic organ prolapse only. The average age (59.3±1.0 vs 59.0±1.0) and mean parity (2.3±1.5 vs 2.6±1.8) were similar in each group. Of note, 109 (26.7%) patients had at least one <30-day postoperative complication. The proportion of patients who had a complication in the combined surgery group and pelvic organ prolapse-only surgery group was similar (27.5% vs 26.0%; P=.82). The Clavien-Dindo scores were similar between the groups (grade I, 10.3% vs 9.3%; grade II, 11.8% vs 12.3%; grade III, 3.9% vs 4.4%; grade IV, 1.0% vs 0%; grade V, 0.5% vs 0%). Patients undergoing combined surgery were less likely to develop postoperative urinary tract infections and urinary retention but were more likely to be treated for wound infections and pelvic abscesses than patients undergoing pelvic organ prolapse-only surgery. After adjusting for combined surgery vs pelvic organ prolapse-only surgery and parity, patients who had anti-incontinence procedures (adjusted odds ratio, 1.85; 95% confidence interval, 1.16-2.94; P=.02) and perineorrhaphies (adjusted odds ratio, 1.68; 95% confidence interval, 1.05-2.70; P=.02) were more likely to have <30-day postoperative complications. Of note, 12 patients in the combined surgery group and 15 patients in the pelvic organ prolapse-only surgery group had subsequent pelvic organ prolapse repairs (5.9% vs 7.4%; P=.26). In the combined surgery group, 10 patients (4.9%) underwent 1 repair, and 2 patients (1.0%) underwent 2 repairs. All patients who had recurrent pelvic organ prolapse surgery in the pelvic organ prolapse-only surgery group had 1 subsequent pelvic organ prolapse repair. Of note, 21 patients in the combined surgery group and 28 patients in the pelvic organ prolapse-only surgery group reported recurrent pelvic organ prolapse (10.3% vs 13.7%; P=.26). On multivariable analysis adjusted for number of previous pelvic organ prolapse repairs, combined surgery vs pelvic organ prolapse-only surgery, and perineorrhaphy at the time of surgery, patients were more likely to have a subsequent pelvic organ prolapse surgery if they had had ≥2 previous pelvic organ prolapse repairs (adjusted odds ratio, 6.06; 95% confidence interval, 2.10-17.5; P=.01). The average follow-up times were 307.2±31.5 days for the combined surgery cohort and 487.7±49.9 days for the pelvic organ prolapse-only surgery cohort. Survival curves indicated that the median time to recurrence was not statistically significant (log-rank, P=.265) between the combined surgery group (4.2±0.4 years) and the pelvic organ prolapse-only surgery group (5.6±0.4 years). CONCLUSION: In this retrospective cohort study, patients undergoing combined pelvic organ prolapse and rectal prolapse surgery had a similar risk of <30-day postoperative complications compared with patients undergoing pelvic organ prolapse-only surgery. Furthermore, patients who underwent combined surgery had a similar risk of recurrent pelvic organ prolapse and subsequent pelvic organ prolapse surgery compared with patients who underwent pelvic organ prolapse-only surgery.

The role of YTH domain containing 2 in epigenetic modification and immune infiltration of pan-cancer.

YTH domain containing 2 (YTHDC2) is the largest N6-Methyladenosine (m6 A) binding protein of the YTH protein family and the only member containing ATP-dependent RNA helicase activity. For further analysing its biological role in epigenetic modification, we comprehensively explored YTHDC2 from gene expression, genetic alteration, protein-protein interaction (PPI) network, immune infiltration, diagnostic value and prognostic value in pan-cancer, using a series of databases and bioinformatic tools. We found that YTHDC2 with Missense mutation could cause a different prognosis in uterine corpus endometrial carcinoma (UCEC), and its different methylation level could lead to a totally various prognosis in adrenocortical carcinoma (ACC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), lung squamous cell carcinoma (LUSC) and UCEC. The main molecular mechanisms of YTHDC2 focused on catalytic activity, helicase activity, snRNA binding, spliceosome and mRNA surveillance. Additionally, YTHDC2 was notably correlated with tumour immune infiltration. Moreover, YTHDC2 had a high diagnostic value for seven cancer types and a prognostic value for brain lower grade glioma (LGG), rectum adenocarcinoma (READ) and skin cutaneous melanoma (SKCM). Collectively, YTHDC2 plays a significant role in epigenetic modification and immune infiltration and maybe a potential biomarker for diagnosis and prognosis in certain cancers.

Discovery of PTN as a serum-based biomarker of pro-metastatic prostate cancer.

Distinguishing clinically significant from indolent prostate cancer (PC) is a major clinical challenge. We utilised targeted protein biomarker discovery approach to identify biomarkers specific for pro-metastatic PC. Serum samples from the cancer-free group; Cambridge Prognostic Group 1 (CPG1, low risk); CPG5 (high risk) and metastatic disease were analysed using Olink Proteomics panels. Tissue validation was performed by immunohistochemistry in a radical prostatectomy cohort (n = 234). We discovered that nine proteins (pleiotrophin (PTN), MK, PVRL4, EPHA2, TFPI-2, hK11, SYND1, ANGPT2, and hK14) were elevated in metastatic PC patients when compared to other groups. PTN levels were increased in serum from men with CPG5 compared to benign and CPG1. High tissue PTN level was an independent predictor of biochemical recurrence and metastatic progression in low- and intermediate-grade disease. These findings suggest that PTN may represent a novel biomarker for the presence of poor prognosis local disease with the potential to metastasise warranting further investigation.

Circ_ROBO2/miR-149 Axis Promotes the Proliferation and Migration of Human Aortic Smooth Muscle Cells by Activating NF-κB Signaling.

Atherosclerosis is the leading global cause of mortality. The occurrence of coronary artery disease (CAD) is regulated by a diversity of pathways, including circRNAs. However, the potential mechanisms of circRNAs in CAD remain unclear. Here, qRT-PCR was used to examine the expressions of miR-149 and circ_ROBO2. Their influences on cell proliferation, migration, and apoptosis were measured by CCK-8, trans-well, and flow cytometry assays, respectively. The protein levels of p-IκBα and NF-κB p65 were examined using western blot. The molecular interactions were validated using dual luciferase reporter and RNA pull-down assays. The expression patterns of circ_ROBO2 and miR-149 in CAD patients and PDGF-BB-treated human aortic smooth muscle cells (HASMCs) were upregulated and downregulated, respectively. Knockdown of circ_ROBO2 could markedly inhibit the capabilities of proliferation and migration, enhance the apoptotic rate, and suppress NF-κB signaling in PDGF-BB-treated HASMCs. Mechanistically, circ_ROBO2 acted as a sponge of miR-149 to activate TRAF6/NF-κB signaling. Rescue studies demonstrated that neither silencing miR-149 nor activation of NF-κB signaling obviously abolished the biological roles of circ_ROBO2 knockdown in PDGF-BB treated-HASMCs. This discovery elucidated a functional mechanism of circ_ROBO2 in CAD, suggesting that circRNAs serve a vital role in the progression of CAD.

Association between preconception paternal health and pregnancy loss in the USA: an analysis of US claims data.

STUDY QUESTION: Is preconception paternal health associated with pregnancy loss? SUMMARY ANSWER: Poor preconception paternal health is associated with a higher risk of pregnancy loss as confirmed in sensitivity analyses accounting for maternal age and health. WHAT IS KNOWN ALREADY: Preconception paternal health can negatively impact perinatal outcomes. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of US insurance claims database from 2009 to 2016 covering 958 804 pregnancies. PARTICIPANTS/MATERIALS, SETTING, METHODS: US insurance claims database including women, men and pregnancies within the USA between 2007 and 2016. Paternal preconception health status (e.g. metabolic syndrome diagnoses (MetS), Charlson comorbidity index (CCI) and individual chronic disease diagnoses) was examined in relation to pregnancy loss (e.g. ectopic pregnancy, miscarriage and stillbirth). MAIN RESULTS AND THE ROLE OF CHANCE: In all, 958 804 pregnancies were analyzed. The average paternal age was 35.3 years (SD 5.3) and maternal age was 33.1 years (SD 4.4). Twenty-two percent of all pregnancies ended in a loss. After adjusting for maternal factors, the risk of pregnancy loss increased with increasing paternal comorbidity. For example, compared to men with no components of MetS, the risk of pregnancy loss increased for men with one (relative risk (RR) 1.10, 95% CI 1.09-1.12), two (RR 1.15, 95% CI 1.13-1.17) or three or more (RR 1.19, 95% CI 1.14-1.24) components. Specifically, less healthy men had a higher risk of siring a pregnancy ending in spontaneous abortion, stillbirth and ectopic pregnancies. Similar patterns remained with other measures of paternal health (e.g. CCI, chronic diseases, etc.). When stratifying by maternal age as well as maternal health, a similar pattern of increasing pregnancy loss risk for men with 1, 2 or 3+ MetS was observed. A statistically significant but weak association between timing of pregnancy loss and paternal health was found. LIMITATIONS, REASONS FOR CAUTION: Retrospective study design covering only employer insured individuals may limit generalizability. WIDER IMPLICATIONS OF THE FINDINGS: Optimization of a father's health may improve pregnancy outcomes. STUDY FUNDING/COMPETING INTERESTS: National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085). M.L.E. is an advisor for Sandstone Diagnostics, Dadi, Hannah and Underdog. No other competing interests were declared. TRIAL REGISTRATION NUMBER: N/A.

Admission white blood cell count predicts post-discharge mortality in patients with acute aortic dissection: data from the MIMIC-III database.

BACKGROUND: Inflammation underlies both the pathogenesis and prognosis in patients with acute aortic dissection (AAD). This study aimed to assess the association of ICU admission of white blood cell count (WBCc) with post-discharge mortality in these patients. METHODS: Clinical data were extracted from the MIMIC-III V1.4 database. After adjusted to covariables, Cox regression analysis and Kaplan-Meier survival curve were performed to determine the relationship between WBCc on admission and post-discharge mortality (30-day, 90-day, 1-year and 5-year) in AAD patients. Subgroup analysis and receiver operating characteristic (ROC) curve analysis were used to test the performance of WBCc in predicting mortality in AAD patients. RESULTS: A total of 325 eligible patients were divided into 2 groups: normal-WBCc group (≤ 11 k/uL) and high-WBCc group (> 11 K/uL). In univariate Cox regression analysis, high WBCc was significant risk predictor of 30-day, 90-day, 1-year and 5-year mortality [hazard ratio (HR), 95% CI, P 2.58 1.36-4.91 0.004; 3.16 1.76-5.70 0.000; 2.74 1.57-4.79 0.000; 2.10 1.23-3.54 0.006]. After adjusting for age and other risks, high WBCc remained a significant predictor of 30-day, 90-day and 1-year mortality in AAD patients (HR, 95% CI, P 1.994 1.058-3.76 0.033; 2.118 1.175-3.819 0.013; 2.37 1.343-4.181 0.003). The area under ROC curve of WBCc for predicting 30-day, 90-day, 1-year and 5-year mortality were 0.69, 0.70, 0.66 and 0.61, respectively. The results from subgroups analysis showed that there was no interaction in most strata and patients who were younger than 69 years of age or had history of respiratory disease with an elevated WBCc had an excess risk of 30-day mortality (HR, 95% CI, P 3.18 1.41-7.14 0.005; 3.84 1.05-14.13 0.043). CONCLUSIONS: Higher than normal WBCc on admission may predict post-discharge mortality in patients with AAD.

Anatomical study of the prostatic urethra using vinyl polysiloxane casts.

BACKGROUND: There are limited studies describing the detailed nonhistologic anatomy of the prostatic urethra. We studied radical prostatectomy specimens to describe the ex vivo anatomical details of its shape and size. METHODS: We conducted an observational study examining the prostatic urethra anatomy. Prostatic urethra casts (molds) were made using vinyl polysiloxane immediately after fresh specimens had been retrieved following prostatectomy for organ-confined prostate cancer. The following measurements were taken from the casts: anterior length, posterior length, maximal diameter, bladder neck to verumontanum, verumontanum to apex length, and prostate urethral angle (PUA). Prostate volume was calculated using the ellipsoid formula: ((p/6) × transverse × length × height). RESULTS: Thirty-three prostatic urethral casts were obtained. The mean prostate volume was 38.59 cc. The mean PUA was 127.6°. The mean transverse, apex, and length of the prostate were 4.65, 4.06, and 3.63 cm, respectively. The mean distance from the verumontanum to sphincter was 1.2 cm. The ratio between the anterior and posterior length of the prostatic urethra was 0.82 cm and did not correlate with prostatic size (Figure 8). CONCLUSION: The distance from the verumontanum to the apex does not change with prostate size; it is uniform with a mean length of 1.2 cm. The anterior length, posterior length, and maximum diameter of the prostatic urethra increase with prostate size. The mean difference between the anterior and posterior length is 0.8 cm and did not correlate with prostate size. Urethral angulation decreased with prostate size but was not significant. Information obtained from this study is of value designing prostatic stents and devices for benign prostatic hyperplasia.

Urinary Stone Disease in Pregnancy: A Claims Based Analysis of 1.4 Million Patients.

PURPOSE: Urinary stone disease during pregnancy is poorly understood but is thought to be associated with increased maternal and fetal morbidity. We determined the prevalence of urinary stone disease in pregnancy and whether it is associated with adverse pregnancy outcomes. MATERIALS AND METHODS: We identified all pregnant women from 2003 through 2017 in the Optum® national insurance claims database. We used diagnosis claims to identify urinary stone disease and assess medical comorbidity. We established the prevalence of urinary stone disease during pregnancy stratified by week of pregnancy. We further evaluated associations among urinary stone disease, maternal complications and pregnancy outcomes in univariable and multivariable analyses. RESULTS: Urinary stone disease affects 8 per 1,000 pregnancies and is more common in white women and women with more comorbid conditions. In fully adjusted models pregnancies complicated by urinary stone disease had higher rates of adverse fetal outcomes including prematurity and spontaneous abortions. This analysis is limited by its retrospective, administrative claims design. CONCLUSIONS: The rate of urinary stone disease during pregnancy is higher than previously reported. Urinary stone disease is associated with adverse pregnancy outcomes.

Parental comorbidity and medication use in the USA: a panel study of 785 000 live births.

STUDY QUESTION: How prevalent is paternal medication use and comorbidity, and are rates of these rising? SUMMARY ANSWER: Paternal medication use and comorbidity is common and rising, similar to trends previously described in mothers. WHAT IS KNOWN ALREADY: Maternal medication use and comorbidity has been rising for the past few decades. These trends have been linked to potential teratogenicity, maternal morbidity and mortality and poorer fetal outcomes. STUDY DESIGN, SIZE, DURATION: This is a Panel (trend) study of 785 809 live births from 2008 to 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used the IBM© Marketscan®™ database to gather data on demographic information and International Classification of Diseases codes and Charlson comorbidity index (CCI) during the 12 months prior to the estimated date of conception for mothers and fathers. We similarly examined claims of prescriptions in the 3 months prior to conception. We performed companion analyses of medications used for >90 days in the 12 months prior to conception and of any medication use in the 12 months prior to conception. MAIN RESULTS AND THE ROLE OF CHANCE: We confirmed that both maternal medication use and comorbidity (e.g. hypertension, diabetes, hyperlipidemia) rose over the study period, consistent with prior studies. We found a concurrent rise in both paternal medication use 3 months prior to conception (overall use, 31.5-34.9% during the study period; P < 0.0001) and comorbidity (CCI of ≥1 and 10.6-18.0% over study period; P < 0.0001). The most common conditions seen in the CCI were chronic obstructive pulmonary disease for mothers (6.6-11.6%) and hyperlipidemia for fathers (8.6-13.7%). Similar trends for individual medication classes and specific comorbidities such as hypertension, diabetes and hyperlipidemia were also seen. All primary result trends were statistically significant, making the role of chance minimal. LIMITATIONS, REASONS FOR CAUTION: As this is a descriptive study, the clinical impact is uncertain and no causal associations may be made. Though the study uses a large and curated database that includes patients from across the USA, our study population is an insured population and our findings may not be generalizable. Mean parental age was seen to slightly increase over the course of the study (<1 year) and may be associated with increased comorbidity and medication use. WIDER IMPLICATIONS OF THE FINDINGS: As parental comorbidity and certain medication use may impact fecundability, temporal declines in parental health may impact conception, pregnancy and fetal outcomes. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

The age of fathers in the USA is rising: an analysis of 168 867 480 births from 1972 to 2015.

STUDY QUESTION: How has the mean paternal age in the USA changed over the past 4 decades? SUMMARY ANSWER: The age at which men are fathering children in the USA has been increasing over time, although it varies by race, geographic region and paternal education level. WHAT IS KNOWN ALREADY: While the rise in mean maternal age and its implications for fertility, birth outcomes and public health have been well documented, little is known about paternal characteristics of births within the USA. STUDY DESIGN, SIZE, DURATION: A retrospective data analysis of paternal age and reporting patterns for 168 867 480 live births within the USA since 1972 was conducted. PARTICIPANTS/MATERIALS, SETTING, METHODS: All live births within the USA collected through the National Vital Statistics System (NVSS) of the Centers for Disease Control and Prevention (CDC) were evaluated. Inverse probability weighting (IPW) was used to reduce bias due to missing paternal records. MAIN RESULTS AND THE ROLE OF CHANCE: Mean paternal age has increased over the past 44 years from 27.4 to 30.9 years. College education and Northeastern birth states were associated with higher paternal age. Racial/ethnic differences were also identified, whereby Asian fathers were the oldest and Black fathers were the youngest. The parental age difference (paternal age minus maternal age) has decreased over the past 44 years. Births to Black and Native American mothers were most often lacking paternal data, implying low paternal reporting. Paternal reporting was higher for older and more educated women. LIMITATIONS, REASONS FOR CAUTION: Although we utilized IPW to reduce the impact of paternal reporting bias, our estimates may still be influenced by the missing data in the NVSS. WIDER IMPLICATIONS OF THE FINDINGS: Paternal age is rising within the USA among all regions, races and education levels. Given the implications for offspring health and demographic patterns, further research on this trend is warranted. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study and there are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Validity of Claims Data for the Identification of Male Infertility.

PURPOSE OF REVIEW: We sought to determine whether infertile men can accurately be identified within a large insurance claims database to validate its use for reproductive health research. RECENT FINDINGS: Prior literature suggests that men coded for infertility are at higher risk for chronic disease though it was previously unclear if these diagnostic codes correlated with true infertility. We found that the specificity of one International Classification of Disease (9th edition) code in predicting abnormal semen parameters was 92.4%, rising to 99.8% if a patient had three different codes for infertility. The positive predictive value was as high as 85%. The use of claims data for male infertility research has been rapidly progressing due to its high power and feasibility. The high specificity of ICD codes for men with abnormal semen parameters is reassuring and validates prior studies as well as future investigation into men's health.

Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts.

The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival. Myelopoiesis increased and was coupled with a reduction in B lymphopoiesis and compromised erythropoiesis, suggesting that hematopoietic lineage/progression was altered. Treatment of mice with acute myeloid or lymphoblastic leukemia with a pharmacologic inhibitor of the synthesis of duodenal serotonin, a hormone suppressing osteoblast numbers, inhibited loss of osteoblasts. Maintenance of the osteoblast pool restored normal marrow function, reduced tumor burden, and prolonged survival. Leukemia prevention was attributable to maintenance of osteoblast numbers because inhibition of serotonin receptors alone in leukemic blasts did not affect leukemia progression. These results suggest that osteoblasts play a fundamental role in propagating leukemia in the marrow and may be a therapeutic target to induce hostility of the niche to leukemia blasts.

Femoral condyle insufficiency fractures: associated clinical and morphological findings and impact on outcome.

OBJECTIVE: To determine the characteristics of femoral condyle insufficiency fracture (FCIF) lesions and their relative associations with the risk of clinical progression. MATERIALS AND METHODS: This HIPAA-compliant retrospective study was approved by our Institutional Review Board. Seventy-three patients (age range, 19-95) were included after excluding patients with post-traumatic fractures, bone marrow infarct, osteochondritis dissecans, or underlying tumor. Two board-certified musculoskeletal radiologists classified morphologic findings including lesion diameter, associated bone marrow edema pattern, and associated cartilage/meniscus damage. Electronic medical charts were evaluated for symptoms, risk factors, and longitudinal outcomes, including total knee arthroplasty (TKA). Imaging characteristics were correlated with clinical findings, and comparison of outcome groups was performed using a regression model adjusted for age. RESULTS: The majority of patients with FCIF were women (64.4%, 47/73), on average 10 years older than men (66.28 ± 15.86 years vs. 56.54 ± 10.39 years, p = 0.005). The most common location for FCIF was the central weight-bearing surface of the medial femoral condyle; overlying full thickness cartilage loss (75.7%, 53/70) and ipsilateral meniscal injury (94.1%, 64/68) were frequently associated. Clinical outcomes were variable, with 23.9% (11/46) requiring TKA. Cartilage WORMS score, adjacent cartilage loss, and contralateral meniscal injury, in addition to decreased knee range of motion at presentation, were significantly associated with progression to TKA (p < 0.05). CONCLUSIONS: FCIF are frequently associated with overlying cartilage loss and ipsilateral meniscal injury. The extent of cartilage loss and meniscal damage, in addition to loss of knee range of motion at the time of presentation, are significantly associated with clinical progression.

Kidney transplantation with early corticosteroid withdrawal: paradoxical effects at the central and peripheral skeleton.

The use of early corticosteroid withdrawal (ECSW) protocols after kidney transplantation has become common, but the effects on fracture risk and bone quality are unclear. We enrolled 47 first-time adult transplant recipients managed with ECSW into a 1-year study to evaluate changes in bone mass, microarchitecture, biomechanical competence, and remodeling with dual energy x-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HRpQCT), parathyroid hormone (PTH) levels, and bone turnover markers obtained at baseline and 3, 6, and 12 months post-transplantation. Compared with baseline, 12-month areal bone mineral density by DXA did not change significantly at the spine and hip, but it declined significantly at the 1/3 and ultradistal radii (2.2% and 2.9%, respectively; both P<0.001). HRpQCT of the distal radius revealed declines in cortical area, density, and thickness (3.9%, 2.1%, and 3.1%, respectively; all P<0.001), trabecular density (4.4%; P<0.001), and stiffness and failure load (3.1% and 3.5%, respectively; both P<0.05). Findings were similar at the tibia. Increasing severity of hyperparathyroidism was associated with increased cortical losses. However, loss of trabecular bone and bone strength were most severe at the lowest and highest PTH levels. In summary, ECSW was associated with preservation of bone mineral density at the central skeleton; however, it was also associated with progressive declines in cortical and trabecular bone density at the peripheral skeleton. Cortical decreases related directly to PTH levels, whereas the relationship between PTH and trabecular bone decreases was bimodal. Studies are needed to determine whether pharmacologic agents that suppress PTH will prevent cortical and trabecular losses and post-transplant fractures.

Role of the gut microbiota in the pathogenesis of endometriosis: a review.

Endometriosis is classically defined as a chronic inflammatory heterogeneous disorder occurring in any part of the body, characterized by estrogen-driven periodic bleeding, proliferation, and fibrosis of ectopic endometrial glands and stroma outside the uterus. Endometriosis can take overwhelmingly serious damage to the structure and function of multi-organ, even impair whole-body systems, resulting in severe dysmenorrhea, chronic pelvic pain, infertility, fatigue and depression in 5-10% women of reproductive age. Precisely because of a huge deficiency of cognition about underlying etiology and complex pathogenesis of the debilitating disease, early diagnosis and treatment modalities with relatively minor side effects become bottlenecks in endometriosis. Thus, endometriosis warrants deeper exploration and expanded investigation in pathogenesis. The gut microbiota plays a significant role in chronic diseases in humans by acting as an important participant and regulator in the metabolism and immunity of the body. Increasingly, studies have shown that the gut microbiota is closely related to inflammation, estrogen metabolism, and immunity resulting in the development and progression of endometriosis. In this review, we discuss the diverse mechanisms of endometriosis closely related to the gut microbiota in order to provide new approaches for deeper exploration and expanded investigation for endometriosis on prevention, early diagnosis and treatment.

Prevalence of pediatric lower urinary tract symptoms in a national claims database of privately insured patients, 2003-2014.

BACKGROUND: We conducted this study to estimate the prevalence of pediatric lower urinary tract symptoms (pLUTS) in a US privately insured pediatric population who are 6-20 years old by age, sex, race/ethnicity from 2003-2014. This has not been previously described in the literature. METHODS: We retrospectively reviewed Optum's de-identified Clinformatics® Data Mart Database between 2003-2014. A pLUTS patient was defined by the presence of ≥ 1 pLUTS-related ICD-9 diagnosis code between the age of 6-20 years. Neurogenic bladder, renal transplant and structural urologic disease diagnoses were excluded. Prevalence by year was calculated as a proportion of pLUTS patients among the total population at risk. Variables reviewed included age, sex, race, geographic region, household factors and clinical comorbidities including attention-deficit/hyperactivity disorder (ADHD), constipation, and sleep apnea. Point of service (POS) was calculated as a proportion of pLUTS-related claims associated with a POS compared to the total claims at all POS in the time period. RESULTS: We identified 282,427 unique patients with ≥ 1 claim for pLUTS between the ages of 6-20 years from 2003 to 2014. Average prevalence during this period was 0.92%, increasing from 0.63% in 2003 to 1.13% in 2014. The median age group of patients was 6-10 years. More patients were female (59.80%), white (65.97%), between 6 and 10 years old (52.18%) and resided in the Southern US (44.97%). Within a single household, 81.71% reported ≤ 2 children, and 65.53% reported ≥ 3 adults. 16.88% had a diagnosis of ADHD, 19.49% had a diagnosis of constipation and 3.04% had a diagnosis of sleep apnea. 75% of pLUTS-related claims were recorded in an outpatient setting. CONCLUSIONS: Families consistently seek medical care in the outpatient setting for pLUTS. The demographic and clinical characteristics of our cohort reflect prior literature. Future studies can help define temporal relationships between household factors and onset of disease as well as characterize pLUTS-related healthcare resource utilization. Additional work is required in publicly insured populations.

Sociodemographic Disparities in Oral Pharmacotherapy Class Utilization Among Medicare Part D Beneficiaries with Overactive Bladder in the United States.

OBJECTIVES: To describe the prevalence of frailty among Medicare beneficiaries with overactive bladder (OAB), analyze oral therapy patterns, and examine potential disparities in treatment. METHODS: This retrospective cohort study utilized the 20% Research Identifiable File Medicare Part D prescription claims dataset (2013-2018). Using the Claims-Based Frailty Index (CFI), Medicare beneficiaries ≥65 years old with OAB were categorized as not frail (CFI <0.15), prefrail (0.15 ≤CFI <0.25), and frail (CFI >0.25). Logistic regression models assessed associations between frailty and pharmacotherapy utilization. RESULTS: Among 111,761 patients (15.8% of the OAB cohort) receiving oral pharmacotherapy (anticholinergic oral medications or mirabegron), 71% were women, 83% were White, and 11.9% were frail. After controlling for age, co-payments and dual eligibility status, frail status (OR 1.16; 95% CI [1.09 - 1.24]), urology (OR 2.05 (95% CI [1.94 - 2.16]) or gynecology (OR 1.74; 95% CI [1.6 - 1.9]) prescribers and residing in the Southern United States (OR 1.53; CI [1.49 - 1.61]) were associated with higher likelihood of mirabegron utilization. Black (OR 0.79; 95% CI ([0.74 - 0.85]) and American Indian/Alaska Native (OR 0.54, 95% CI ([0.39 - 0.74]) patients were less likely to utilize mirabegron than White beneficiaries. CONCLUSION: Frail beneficiaries and those with urology and gynecology prescribers showed higher likelihoods of beta-3 agonist utilization. Despite adjustments, Black and AI/AN patients were less likely to fill mirabegron prescriptions, suggesting disparities in treatment. Our findings highlight the need for policies, interventions, and initiatives to promote equitable OAB oral therapy utilization in vulnerable populations.