bluuebunny/crossref_metadata_2025 huggingface dataset:
FC008: Sex Difference in COVID-19 Mortality Risk among Patients on Kidney Function Replacement Therapy
Authors: Vart Priya , Duivenvoorden Raphael , Jager Kitty J , Noordzij Marlies , Gansevoort Ronald
Published: May 2022

BACKGROUND AND AIMS

In the general population with COVID-19, male sex is an established risk factor for mortality. A more robust immune response to COVID-19 in women has been suggested to be one of the factors explaining this sex difference in mortality. Patients on kidney function replacement therapy (KFRT) have an impaired immune response, especially kidney transplant recipients due to their use of immunosuppressants. In this study, we therefore examined whether male sex is still a risk factor for mortality among patients on KFRT with COVID-19.

METHOD

Data were used from the European Renal Association COVID-19 Database (ERACODA) of kidney transplant recipients and dialysis patients who presented with COVID-19 between 1 February 2020 and 30 April 2021. The primary study outcome was 3-month mortality. As secondary outcomes, in-hospital mortality and 28-day mortality were examined. Associations were investigated using multivariable Cox proportional-hazards regression analysis. Assuming immunosuppressant use is among the main factors contributing to excess mortality in kidney transplant recipients compared with dialysis patients, we also investigated the association of type of KFRT with mortality by sex.

RESULTS

ERACODA included 1204 kidney transplant recipients (male: 62.0%, mean age: 56.4 years) and 3206 dialysis patients (male: 61.8%, mean age: 67.7 years). Three-month mortality in kidney transplant recipients was 16.9% in males and 18.6% in females (P = 0.31) and in dialysis patients 27.1% in males and 21.9% in females (P = 0.001). In a model adjusted for age, frailty, smoking and comorbidities, the aHR for the risk of 3-month mortality in males (versus females) was 0.87 (95% CI: 63, 1.21, P = 0.41) in kidney transplant recipients and 1.32 (95% CI: 1.13, 1.55, P = 0.001) in dialysis patients (P for interaction = 0.03). In a fully adjusted model, the aHR for the risk of 3-month mortality in kidney transplant recipients (versus dialysis patients) was 1.26 (95% CI: 1.02, 1.56, P = 0.03) in males and 1.73 (95% CI: 1.31, 2.27, P < 0.001) in females (p for interaction = 0.03). Essentially similar results were obtained for in-hospital mortality and 28-day mortality.

CONCLUSION

In patients on kidney function replacement therapy with COVID-19, male sex is not a risk factor for mortality among kidney transplant receipts but remains a risk factor among dialysis patients. The use of immunosuppressants in kidney transplant recipients, among other factors, may have narrowed the difference in the immune response to COVID-19 between men and women, and therefore reduced the sex difference in COVID-19 mortality risk.
FC026: Chronic High Phosphate Level Impairs Cardiac Health
Authors: Grund Andrea , Vogt Isabel , Sophie Richter Gloria , Richter Beatrice , Trogisch Felix , Martin Garrido Abel , Heineke Jörg , Dittrich-Breiholz Oliver , Haffner Dieter , Leifheit-Nestler Maren
Published: May 2022

BACKGROUND AND AIMS

Patients with chronic kidney disease (CKD) suffer from disturbed mineral metabolism in which the chronic phosphate load leads to the elevation of the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). Persistent hyperphosphatemia predisposes to cardiovascular events and increased morbidity and mortality rates. It is discussed that even in the general population, consumption of highly processed food increases phosphate level, which in turn may increase cardiovascular risk. Here, we aim to elucidate the pathological mechanisms of how chronic high phosphate intake mediates cardiac remodeling and dysfunction, respectively.

METHOD

Male C57BL/6 wild type mice received a high phosphate diet containing 2% inorganic phosphate (HPD) or a 0.8% normal phosphate diet (NPD) for 6 months. Echocardiographic analysis and ex-vivo measurements in cardiomyocytes using IonOptix system were assessed to evaluated cardiac function and contractility. Bulk RNA sequencing of whole heart tissue followed by pathway analysis was done to identify affected relevant signaling pathways, which were verified by in vitro studies using neonatal rat ventricular myocytes (NRVM).

RESULTS

Chronic phosphate overload resulted in increased level of serum and urinary phosphate and high plasma PTH and FGF23 concentrations. HPD caused impaired heart function as shown by reduced ejection fraction, increased end-systolic volumes and enlarged systolic left ventricular internal diameter accompanied by impaired left ventricular relaxation as seen in Doppler echocardiography. Histological analysis showed increased cardiomyocyte area and length in HPD-fed mice compared with NPD demonstrating cellular hypertrophy. RNA sequencing revealed differentially expressed genes of calcium signaling pathways in the HPD group. Besides, immunoblot analysis of whole heart tissue showed altered Phospholamban activity after 6 months of HPD compared with NPD, indicating altered calcium pump in cardiomyocytes. Preliminary analysis of sarcomere movements and changes of intracellular calcium levels in single cardiomyocytes isolated from NPD and HPD mice after 6 months suggested impaired contractility. Detailed results will be presented here.

 In vitro stimulation of isolated NRVM with high phosphate induced a hypertrophic growth response, verifying a direct effect of high phosphate on the heart.

CONCLUSION

HPD in mice causes a dilated cardiac phenotype including cellular hypertrophy, altered contractility and differentially expressed genes involved in calcium signaling pathways, indicating that a chronic high phosphate load is harmful for the heart also in the general population.
FC039: Associations between Maternal Antenatal Systemic Glucocorticoids Usage and Childhood Chronic Kidney Disease
Authors: Hsu Chien-Ning , Tain You-Lin
Published: May 2022

BACKGROUND AND AIMS

The effect of antenatal glucocorticoid exposure on offspring health is currently unclear. Therefore, this study examined the association of maternal exposure to systemic glucocorticoids in the past and during pregnancy with the risk of chronic kidney disease (CKD) development in childhood.

Methods

A retrospective cohort study of maternal-child dyads was identified from the largest healthcare delivery system in Taiwan between 1 January 2004 and 31 December 2018. Primary analyses were used to compare past and gestational exposures with non-exposure to systemic glucocorticoid considering an inverse probability of treatment weight to adjust the hazard ratio of offspring CKD development in singleton child-matched pairs. Offspring birthweight, sex, gestational weeks stratified analyses and sibling-matched sensitivity analyses were performed to ensure the robustness of the primary study results.

RESULTS

In a cohort with 31 927 singleton born children, the cumulative incidence of CKD was 2.23% (n = 713), with 3.18% (n = 63) in the gestational glucocorticoid-exposed group, 1.91% (n = 58) in the past exposed group and 2.2% (n = 592) in the non-exposed group. Gestational exposure, compared with non-exposure, was significantly associated with a higher risk of childhood CKD (inverse probability therapeutic weighted hazard ratio [wHR], 1.42 [95% confidence interval (95% CI) 1.05–1.92] in Figure. 1A, but not past exposure (wHR: 0.89, 95% CI 0.67–1.18) (Figure. 1B). In male children, the risk of CKD was significantly higher among gestational-exposed children than among unexposed children (wHR: 1.72, 95% CI 1.21–2.43). The cohort with sibling matched children did not show a significantly increased risk of childhood CKD associated with gestational exposure (wHR: 1.31, 95% CI 0.79–2.18) (Figure. 1A).

CONCLUSION

Maternal gestational glucocorticoid treatment was found to be significantly associated with CKD development in children. These findings may support clinicians in performing benefit-risk assessment and in decision-making for systemic glucocorticoid treatment during pregnancy, in clinical settings.
FC076: Development of a High-Throughput in Vivo Drug Screening Assay Using a FSGS-Like Zebrafish Model
Authors: Schindler Maximilian , Siegerist Florian , Lange Tim , Bach Sophia-Marie , Klawitter Marianne , Gehrig Jochen , Ellinger Bernhard , Gul Sheraz , Endlich Nicole
Published: May 2022

BACKGROUND AND AIMS

Focal segmental sclerosis (FSGS) is a severe histopathological condition which often results in end-stage renal disease. Loss of podocytes and severe changes of podocyte foot process morphology accompanied by proteinuria are the hallmarks of FSGS. Since no therapeutic agents are available until now, further efforts must be made to identify new drugs to treat this disease. The zebrafish larva is a widely used kidney research model as the morphology and function of zebrafish and mammalian glomeruli are very similar. Since our group has already established a FSGS-like zebrafish injury model based on the nitroreductase-metronidazole cell ablation system, we have developed a high-throughput based in vivo drug screening assay.

METHOD

We used a zebrafish screening strain that expresses mCherry and the bacterial enzyme nitroreductase in podocytes. Additionally, a circulating vitamin-D-binding eGFP fusion protein with a size of 78 kDa is expressed and serves as a read-out for proteinuria. Incubation with 80 µM metronidazole for 24 h at 4 days post-fertilization (dpf) induces an FSGS-like phenotype in these larvae. A library of 138 epigenetic drugs were screened and the results are presented herein. Groups of 12 larvae received injury induction as well as drug treatment and were transferred individually into 96-well plates prepared with custom agarose molds. Larvae were oriented laterally and imaged with a high-content screening microscope (Acquifer Imaging Machine). The eGFP signal in the caudal vasculature as well as the glomerular mCherry signal served as readout systems. At 6 dpf, the same larvae and regions were imaged again. Custom written FIJI codes automatically segmented and measured the fluorescence intensities of both readouts and timepoints. For each larva, intensity ratios were determined and the ratios of each treatment group served as the input for statistical analysis.

RESULTS

Treatment for 24 hours with 80 µM metronidazole resulted in a measurable decline of the eGFP signal in the vasculature and of the podocyte mCherry signal compared to the vehicle (DMSO) group. Simultaneous treatment of metronidazole with the 138 drugs in the epigenetics library resulted in beneficial outcomes in varying degrees (9 drugs were positive, 36 compounds were lethal).

CONCLUSION

This new in vivo semi-automated high-throughput compatible drug screening assay allows rapid identification of FSGS protective drugs. Here we screened 138 epigenetic drugs, which led to the identification of 9 potential drugs which have had a beneficial effect on podocytes and/or the glomerular filtration barrier.
FC 100: Echocardiography: A Promising Screening and Monitoring Tool for Central Venous Stenosis in Hemodialysis Patients
Authors: Liao Ruoxi , Wang Hui , Wang Shanshan , Cui Tian-Lei , Fu Ping
Published: May 2022

BACKGROUND AND AIMS

Central venous stenosis (CVS) is a common but underestimated complication of vascular access in hemodialysis (HD) patients. The objective of this study was to compare the diagnostic efficacy of echocardiography and computed tomography angiography (CTA) for CVS in HD patients with access dysfunction.

METHOD

This was a retrospective study. HD patients with access dysfunction admitted to our institute between 1 April 2021 and 31 October 2021 were enrolled. Echocardiography, CTA and digital subtraction angiography (DSA) were performed to assess CVS. Receiver operator characteristic analysis was performed to compare the diagnostic efficacy of echocardiographic parameters and CTA for CVS, with DSA results as the reference standard.

RESULTS

A total of 167 HD patients (70 males, age 63 ± 13 years) were enrolled, among whom 99 (59%) were diagnosed with CVS based on DSA and only 9 presented with significant clinical symptoms of CVS. Among all of the echocardiographic parameters, superior vena cava (SVC) diameter showed the highest efficacy for CVS diagnosis (cut-off value ≤12 mm, specificity 70%, sensitivity 77%), which was equivalent to CTA (AUC 0.79 versus 0.81; P = 0.646) (Figure 1A). Some of the other echocardiographic parameters, including maximal and minimal right atrial volume (RAV), also showed moderated diagnostic efficacy for CVS. The specificity and sensitivity increased when echocardiography and CTA were used to diagnose brachiocephalic vein and SVC stenosis instead of total CVS (Figure 1B). Patients with CVS had a smaller SVC diameter (9.8 ± 3.5 mm versus 13.7 ± 3.3 mm;  P < 0.001) and a reduced right RAV [RAV max median 20 (interquartile range 15–27) mL versus 31(24–39) mL; P < 0.001; RAV min 8 (5–10) mL versus 14 (10–17) mL; P < 0.001] compared with non-CVS patients. Spearman's rank correlation showed a significant negative correlation between RAV and hemodialysis vintage.

CONCLUSION

With equivalent diagnostic power for CVS to CTA, echocardiography has the potential to be used as a screening and monitoring tool for CVS in HD patients with access dysfunction.
FC 102: Daily Phosphorus Intake, its Source and Mortality in Adults on Hemodialysis: The Diet-Hd Study
Authors: Su Guobin , Saglimbene Valeria , Bernier-Jean Amélie , Wong Germaine , Natale Patrizia , Ruospo Marinella , Craig Jonathan , Hegbrant Jorgen , Jesus Carrero Juan , Strippoli Giovanni
Published: May 2022

BACKGROUND AND AIMS

Elevated serum phosphorus is associated with increased mortality in dialysis patients. Since the bioavailability of dietary phosphorus intake (DPI) varies based on its source and might contribute to serum phosphorus differently, the aim of the study is to investigate the association between total DPI and DPI from different sources with mortality in patients treated with hemodialysis.

METHOD

DPI (plant, animal and other sources) was ascertained by the Global Allergy and Asthma European Network food frequency questionnaire within the DIET-HD study, a multinational cohort study of European and South American adults on maintenance hemodialysis. Adjusted Cox regression analyses were conducted to evaluate the association between total and source-specific DPI (both as tertiles and continuous in fraction or in absolute amount) with all-cause and cardiovascular mortality.

RESULTS

A total of 8110 patients were followed for a median of 3.8 years (26 074 person-years). There were 2953 deaths, of which 1160 were cardiovascular-related. The median (interquartile range) DPI was 1388 (961–1994) mg/day, with only 12% (995/8110) of participants consuming the recommend range of DPI (800–1000 mg/day). Each standard deviation (SD, 896 mg/day) increase in total DPI was associated with higher all-cause mortality [hazard ratio (HR) 1.14; 95% confident interval (95% CI) 1.02–1.27] and cardiovascular mortality (1.45; 95% CI 1.08–1.96). Each SD (17%) increase in the fraction of DPI from plant sources was associated with lower all-cause mortality (HR 0.92; 95% CI 0.85–0.99) and marginally in cardiovascular mortality (HR 0.93; 95% CI 0.85–1.01). Each SD (9%) increase in the fraction of DPI from other source [HR: 1.06; 95%CI 1.02–1.10)] was associated with higher all-cause mortality. In contrast, each SD (17%) increase in the fraction of DPI from animal source was not associated either all-cause (HR: 1.02; 95% CI 0.96–1.07) or cardiovascular mortality (HR 1.07; 95% CI 0.98–1.16). Increased absolute amount of DPI from animal or other source were associated with both all-cause and cardiovascular mortality.

CONCLUSION

A higher total DPI is associated with increased all-cause and cardiovascular death. This positive association is driven by the DPI from animal and other sources, while higher DPI fraction from plant associated with reduced all-cause mortality.
FC 117: Clinical Validation of Automated Urinary Chemokine Assays for Non-Invasive Detection of Kidney Transplant Rejection: A Large Prospective Cohort Study
Authors: Van Loon Elisabet , Tinel Claire , Callemeyn Jasper , Coemans Maarten , Van Craenenbroeck Amaryllis , Vaulet Thibaut , Anglicheau Dany , Naesens Maarten
Published: May 2022

BACKGROUND AND AIMS

The urinary chemokines CXCL9 and CXCL10 have been extensively studied as biomarkers for kidney transplant rejection. However, final validation in a sufficiently large, real-world prospective cohort is needed to determine the relation to rejection subtypes and clinical confounders, the context of use and the added benefit for clinical practice.

METHOD

In this single-centre prospective cohort study, we analysed 1559 biopsy-paired urine samples at both indication and protocol time points from 622 kidney transplants performed between April 2013 and July 2019. We quantified urinary CXCL9 and CXCL10 using automated immunoassays and normalized the values to urinary creatinine. In addition to evaluating diagnostic performance for Banff-grade rejection, we also considered rejection as assessed by the molecular microscope.

RESULTS

The urinary chemokines strongly associated with the inflammation severity in the biopsy, when considering classical semi-quantitative histological scores, but also when considering molecular rejection scores. The diagnostic performance of urinary chemokines alone was moderate for Banff acute rejection, and increased when considering treated rejection or molecular rejection instead (Figure 1). Taking into account confounding factors rather than excluding them, an integrated model of urinary chemokines with eGFR, donor-specific antibodies, time post-transplant and polyoma viremia had a high diagnostic value for acute rejection (N = 150) [ROCAUC 82.6%, 95% confidence interval (95% CI) 78.9–86.2] and added value on top of clinical standard-of-care. The integrated score would help to safely avoid 59 protocol biopsies per 100 patients when the predicted rejection risk is less than 10%.

CONCLUSION

The integration of urinary chemokines and clinical markers allows for personalized noninvasive monitoring of rejection probability and enables to importantly and safely reduce the number of unnecessary biopsies. We expect this study to pave the way for the final implementation of urinary chemokine measurements as noninvasive markers of rejection in routine clinical follow-up after kidney transplantation.
MO084: Resistant Hypertension is Associated With an Increased Cardiovascular Risk Compared to Patients Controlled on a Similar Multi-Drug Regimen
Authors: Leiba Adi , Angel-Korman Avital
Published: May 2022

BACKGROUND AND AIMS

The long-term risk associated with resistant hypertension as compared with other phenotypes of hypertension is still unclear. This has been a result of heterogeneity in the definition of both resistant and non-resistant hypertension. We aimed at assessing the cardiovascular and renal outcomes of resistant hypertension compared with a similarly treated (≥3 medication classes including a diuretic) patients whose blood pressure is under control.

METHOD

This retrospective cohort study utilized the computerized database of Maccabi Healthcare Services (MHS). Over a 10 years follow up, a historical cohort of patients with baseline uncontrolled resistant hypertension were compared to a similar cohort of hypertensive examinees, whose BP was well controlled. Clinical outcomes were assessed using Cox regression multivariable analyses.

RESULTS

—A total of 1487 patients (50% males, mean age at baseline = 68.3 ± 10.4 years) were included in the resistant hypertension cohort and 1343 patients (50% males, 66.2 ± 10.6y) in the controlled hypertension reference group. After adjusting for age, sex, BMI and patients’ comorbidities, uncontrolled resistant hypertension was associated with a hazard ratio (HR) of 1.35 (95% CI: 1.08–1.69) for incidence of ischemic heart disease and 1.51 (1.06–2.16) for secondary cardiovascular events compared to the reference group. It also was associated with an increased risk of stroke or TIA (HR = 1.36; 95% CI: 1.00–1.86). Patients with resistant hypertension had more hospitalization days (mean = 4.2 days versus 3 days per year, P < 0.001), and more emergency room visits during follow-up period (83.3% versus 77%, P < 0.001). Overall, uncontrolled resistant hypertension was associated with a 19% (95% CI: 11–29%) increase in the direct healthcare expenditure during the first year of follow-up.

CONCLUSION

Resistant hypertension is associated with a 35% increased risk of both cardiovascular and cerebrovascular events, when compared with a similarly treated hypertensive patients whose blood pressure is under control. Physicians should overcome therapeutic inertia and add a fourth or a fifth anti-hypertensive medication, even when treating patients who are already on a multi-drug regimen.
MO088: Peridialytic and Intradialytic Blood Pressure Measurements are Not Valid Estimates of 44-Hour Ambulatory Blood Pressure in Patients With Intradialytic Hypertension
Authors: Theodorakopoulou Marieta , Eleni Alexandrou Maria , Iatridi Foteini , Karpetas Antonios , Geladari Virginia , Pella Eva , Alexiou Sofia , Ziakka Stavroula , Papagianni Aikaterini , Sarafidis Pantelis
Published: May 2022

BACKGROUND AND AIMS

In contrast with pre- and post-dialysis blood pressure (BP), intradialytic and home BP measurements are accurate metrics of ambulatory BP load in hemodialysis patients. This study assessed the agreement of peridialytic, intradialytic and scheduled interdialytic recordings with 44-h interdialytic BP in a distinct hemodialysis population, patients with intradialytic-hypertension (IDH).

METHOD

45 patients with IDH (defined as: SBP rise ≥ 10 mmHg from pre- to post-dialysis and post-dialysis SBP ≥ 150 mmHg) with valid 48-h ABPM and 197 without IDH were included in this analysis. With 44-h BP used as reference method, we tested the accuracy of the following BP metrics: Pre- and post-dialysis, intradialytic, intradialytic plus pre/post-dialysis readings and scheduled interdialytic BP (out-of-dialysis day: readings at 8:00 am, 8:00 pm or their average).

RESULTS

In patients with IDH, peri-dialytic and intradialytic BP metrics showed at best moderate correlations, while averaged-interdialytic-SBP/DBP exhibited strong correlation (r = 0.882/r = 0.855) with 44-h SBP/DBP. Bland-Altman plots showed large between-method difference for peri- and intradialytic BP, but only + 0.7 mmHg between-method difference and good 95% limits-of-agreement for averaged-interdialytic-SBP. The sensitivity/specificity and κ-statistic for diagnosing 44-h SBP ≥ 130 mmHg were low for pre-dialysis (72.5%/40.0%, κ-statistic = 0.074) and post-dialysis (90.0%/0.0%, κ-statistic = −0.110), intradialytic (85.0%/40.0%, κ-statistic = 0.198) and intradialytic plus pre/post-dialysis SBP (85.0%/20.0%, κ-statistic = 0.043). Averaged-interdialytic-SBP showed high values of sensitivity/specificity (97.5%/80.0%) and strong agreement (κ-statistic = 0.775). In ROC-analyses, the peri- and intradialytic BP metrics showed bad performance with low Area-Under-the-Curve values; scheduled interdialytic SBP/DBP had the largest AUC (0.967/0.951), along with the highest sensitivity(90.0%/88.0%) and specificity(100.0%/90.0%) for detecting elevated 44-h BP.

CONCLUSION

In patients with IDH, averaged-scheduled-interdialytic but not pre- and post-dialysis, nor intradialytic BP recordings show reasonable agreement with ambulatory BP. Interdialytic BP recordings only could be used for hypertension diagnosis and management in these subjects.
FC 131: Kidney Injury Molecule-1-Mediated Small Extracellular Vesicles Uptake is Crucial for Renal Tubulointerstitial Inflammation
Authors: Chen Jun , Tang Tao-Tao , LI Zuolin , Wang Cui , Shen Anran , Liu Bicheng , LV Linli
Published: May 2022

BACKGROUND AND AIMS

Tubular epithelial cells (TECs) exposed to hypoxia during kidney injury communicate with interstitial inflammatory cells and contribute to tubulointerstitial inflammation. However, whether injured TECs communicate under hypoxia in an autocrine or paracrine manner and contribute to tubulointerstitial inflammation has yet to be identified moieties. The purpose of this study is to explore the role of small extracellular vesicles(sEVs) secreted by hypoxic TECs in the development of renal tubulointerstitial inflammation and the mechanism of sEV-mediated TEC communication.

METHOD

Ischemia reperfusion induced kidney injury (IRI) models were established to explore the conditions of hypoxia induced Inflammation as well as tubular kidney injury molecule-1(KIM-1) expression and sEV production. In vitro, hypoxic TEC-derived sEVs (Hypo-sEVs) were applied to culture TECs to explore sEV-mediated tubule communication. Besides, inflammatory cytokine generation was analyzed in hypoxic TECs with silence of KIM-1 and Rab27a. To investigate the mechanism of sEV internalization, uptake efficiency of the recipient TECs was evaluated in conditions of KIM-1 overexpression. Phosphatidylserine (PS) on the surface of Hypo-sEVs was further assayed by nanoflow cytometry (NanoFCM). sEVs isolated from hypoxic TECs with or without labeling were transferred to IRI mice to detect its localization and the consequences on tubulointerstitial inflammation.

RESULTS

In IRI mice, hypoxia induced tubule injury as evidenced by tubule HIF-1α and KIM-1 expression as well as tubulointerstitial inflammation were observed. Impressively, we noticed the colocalization of sEV marker (CD63) with KIM-1, which suggested increased sEV production in injured tubules or uptake of sEVs by damaged tubules through KIM-1. Intriguingly, KIM-1 expression also correlated with CD3 + and CD68 + inflammatory cells infiltration. In vitro, stable HIF-1α and KIM-1 expression was detected in hypoxic TECs with significant inflammatory cytokine expression. Notably, increased sEV release was noticed in hypoxic TECs, while hypoxia induced inflammation could be ameliorated when KIM-1 and Rab27a were silenced. Importantly, the inflammatory response of hypoxic TECs induced by exogenous Hypo-sEVs could be partly relieved when KIM-1 was knock down by siRNA transfection. Besides, PS could readily be detected in Hypo-sEVs by NanoFCM suggesting that sEVs may accelerate TEC inflammation via recognizing PS by KIM-1. Correspondingly, Hypo-sEVs localized to tubules with KIM-1 expression and amplified tubulointerstitial inflammation in IRI mice.

CONCLUSION

Our studies demonstrate that KIM-1 expressed by injured tubules mediates sEVs uptake via recognizing PS, which participates in TEC communication and augment of tubulointerstitial inflammation induced by hypoxia.
FC 132: Deficiency of Proximal Tubular Cyclin-Dependent Kinase 12 Exacerbates Kidney Injury Through DNA-Damage Response
Authors: Zhang Yilin , Wang Bin , Liu Bicheng
Published: May 2022

BACKGROUND AND AIMS

Acute kidney injury (AKI) is a frequent, serious condition characterized by acute tubular necrosis involving the destruction of tubular epithelial cells. Recent studies have shown that DNA damage contributes to renal tubular cell death during kidney injury. Cyclin-dependent kinase 12 (CDK12) is a member of the cyclin-dependent kinase family that phosphorylates the carboxy-terminal domain of RNA polymerase II and selectively regulates transcription of DNA-damage response (DDR) genes. CDK12 inhibitor was reported to play an important role in a variety of cancers. So far, the functions of CDK12 deficiency in the pathogenesis of AKI have not been studied.

METHOD

Here, we established a cisplatin-induced AKI mouse model with CDK12 knockdown mice and created stable in vitro models with CDK12 knockdown tubular epithelial cells. Cisplatin nephrotoxicity was induced by intraperitoneal injection of cisplatin (20 mg/kg). After 2 days following cisplatin treatment, blood and kidney tissues were harvested. Renal function and histology were evaluated. DDR, tubular apoptosis, cell proliferation were evaluated by immunofluorescence assays, real-time PCR, flow cytometer and western blot analysis.

RESULTS

Here we found that CDK12 was downregulated in the renal tubular epithelial cells of AKI patients and murine AKI models and associated with kidney functions. RNA-sequencing of kidney cortex demonstrated increased transcripts involved in DDR and tubular apoptosis signaling pathways and decreased transcripts cell proliferation pathways, in knockout versus control mice. Moreover, more severe AKI occurred in tubular cell-specific knock-down of CDK12 mice (CDK12RTEC+/–) than age- and sex-matched wild type mice, as evidenced by increased levels of serum creatinine (Scr), blood urea nitrogen (BUN) and tubular injury score. Mechanistically, CDK12 deficiency accelerated cisplatin-induced DDR, mitochondrial apoptosis and abrogates cell proliferation of renal tubular cells in these mice. Similar results were observed after the human renal tubular epithelial cell line HK-2 cells exposure to CDK12 siRNA stimulation. In contrast, lentivirus-mediated CDK12 overexpression protected against DDR and mitochondrial apoptosis while attenuating renal dysfunction, morphological damage and renal tubular cell death in cisplatin-induced AKI models. Moreover, representative Integrative Genomics Viewer (IGV) profiles demonstrated a minimal impact of gene length-dependent elongation defects, a substantial proportion of which participate in the DDR and cell proliferation.

CONCLUSION

Thus, proximal tubule-specific deficiency of CDK12 exacerbates acute kidney injury and tubular apoptosis, likely due to affecting the expression of genes involved in the DDR and mRNA processing.
What is a Good School, and Can Parents Tell? Evidence on the Multidimensionality of School Output
Authors: Beuermann Diether W , Jackson C Kirabo , Navarro-Sola Laia , Pardo Francisco
Published: May 2022

To explore whether schools’ causal impacts on test scores measure their overall impact on students, we exploit plausibly exogenous school assignments and data from Trinidad and Tobago to estimate the causal impacts of individual schools on several outcomes. Schools’ impacts on high-stakes tests are weakly related to impacts on important outcomes such as arrests, dropout, teen motherhood, and formal labour market participation. To examine if parents’ school preferences are related to these causal impacts, we link them to parents’ ranked lists of schools and employ discrete-choice models to infer preferences for schools. Parents choose schools that improve high-stakes tests even conditional on peer quality and average outcomes. Parents also choose schools that reduce criminality and teen motherhood and increase labour market participation. School choices among parents of low-achieving students are relatively more strongly related to schools’ impacts on non-test-score outcomes, while the opposite is true for parents of high-achieving students. These results suggest that evaluations based solely on test scores may be misleading about the benefits of school choice (particularly for low-achieving students), and education interventions more broadly.
THE EFFECTS OF CONE-BEAM COMPUTED TOMOGRAPHY IMAGING GUIDANCE ON PATIENT RADIATION EXPOSURES IN TRANS-ARTERIAL CHEMOEMBOLISATION FOR HEPATOCELLULAR CARCINOMA
Authors: Wong S Y , Foley S , Cantwell C P , Ryan R , Lucey J , Maher P , McNulty J P
Published: May 2022

This study investigated the effects of cone-beam computed tomography (CBCT) guidance in trans-arterial chemoembolisation (TACE) procedures on the number of digital subtraction angiography (DSA) runs acquired and total patient radiation exposure in patients with hepatocellular carcinoma (HCC). A retrospective, analytical cross-sectional, single institution, study was conducted. Dose data were compared across the control (DSA guidance alone) and study (DSA and CBCT guidance) groups. A total of 122 procedures were included within the study. There was a significant reduction in the number of DSA runs (3 vs 5, p < 0.001) and DSA air kerma-area product (PKA) (3077.3 vs 4276.6 μGym2, p = 0.042) for the study group when compared to the control group. Total procedural PKA and total procedural reference air kerma (Ka,r) were shown to be 50 and 73% higher, respectively, for the study group when compared to the control group. CBCT imaging guidance does reduce the number of DSA runs and DSA PKA required to complete the TACE procedure for patients diagnosed with HCC; however, a substantial increase in total procedural PKA is to be expected and it is thus important that this increased dose is carefully considered and justified.
How can trust succeed in an era of mistrust?
Authors: Liechtenstein H S H Prince Michael of
Published: May 2022

This article aims to highlight the importance of trust for a prosperous society and economy, and related to that, the role and duties of the international fiduciary trust industry. Furthermore, the article explains when private wealth becomes a key enabler of effective sustainability.
Low-dose silver nanoparticles plus methyl mercury exert embryotoxic effects on mouse blastocysts via endoplasmic reticulum stress and mitochondrial apoptosis
Authors: Huang Chien-Hsun , Wang Fu-Ting , Chan Wen-Hsiung
Published: May 2022

The health and environmental impacts of the increasing commercial use of silver nanoparticles (AgNPs) are a growing concern. Methyl mercury (MeHg) is a potent toxin that biotransforms from mercury or inorganic mercury compounds in waterways and causes dangerous environmental contamination. However, the potential interactions and combined effects of AgNPs and MeHg are yet to be established. In the current study, we showed that low/non-embryotoxic doses of AgNPs and MeHg interact synergistically to induce embryotoxicity and further explored the underlying mechanisms affecting mouse embryo development. Notably, co-treatment with noncytotoxic concentrations of AgNPs (10 μM) and MeHg (0.1 μM) triggered apoptotic processes and embryotoxicity in mouse blastocysts and evoked intracellular reactive oxygen species (ROS) generation, which was effectively blocked by preincubation with 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox), a classic antioxidant. Further experiments demonstrated that ROS serve as a key upstream inducer of endoplasmic reticulum (ER) stress and mitochondria-dependent apoptotic processes in AgNP/MeHg-induced injury of mouse embryo implantation and pre- and postimplantation development. Our results collectively indicate that AgNP and MeHg at non-embryotoxic concentrations can synergistically evoke ROS, ultimately causing embryotoxicity through promotion of ER stress and mitochondria-dependent apoptotic signaling cascades.
Genome-wide transcriptome analysis reveals the regulatory network governing terpene trilactones biosynthesis in Ginkgo biloba
Authors: Ye Jiabao , Yang Ke , Li Yuting , Xu Feng , Cheng Shuiyuan , Zhang Weiwei , Liao Yongling , Yang Xiaoyan , Wang Lina , Wang Qijian
Published: May 2022

Ginkgo biloba L. is currently the only remaining gymnosperm of the Ginkgoaceae Ginkgo genus, and its history can be traced back to the Carboniferous 200 million years ago. Terpene trilactones (TTLs) are one of the main active ingredients in G. biloba, including ginkgolides and bilobalide. They have a good curative effect on cardiovascular and cerebrovascular diseases because of their special antagonistic effect on platelet-activating factors. Therefore, it is necessary to deeply mine genes related to TTLs and to analyze their transcriptional regulation mechanism, which will hold vitally important scientific and practical significance for quality improvement and regulation of G. biloba. In this study, we performed RNA-Seq on the root, stem, immature leaf, mature leaf, microstrobilus, ovulate strobilus, immature fruit and mature fruit of G. biloba. The TTL regulatory network of G. biloba in different organs was revealed by different transcriptomic analysis strategies. Weighted gene co-expression network analysis (WGCNA) revealed that the five modules were closely correlated with organs. The 12 transcription factors, 5 structural genes and 24 Cytochrome P450 (CYP450) were identified as candidate regulators for TTL accumulation by WGCNA and cytoscape visualization. Finally, 6 APETALA2/ethylene response factors, 2 CYP450s and bHLH were inferred to regulate the metabolism of TTLs by correlation analysis. This study is the comprehensive in authenticating transcription factors, structural genes and CYP450 involved in TTL biosynthesis, thereby providing molecular evidence for revealing the comprehensive regulatory network involved in TTL metabolism in G. biloba.
Direct-to-Consumer Prenatal Testing for Multigenic or Polygenic Disorders: A Position Statement of the American College of Medical Genetics and Genomics (ACMG)
Authors:   ACMG Board of Directors
Published: May 2022

(Abstracted from Genet Med 2021:23:2027–2028)

The American College of Medical Genetics and Genomics (ACMG) recently updated its position statement on direct-to-consumer (DTC) prenatal testing for multigenic or polygenic disorders. The ACMG recommends that prenatal testing for these disorders is not ready for use in the clinic and should not be offered as DTC testing.
Intrinsic or Invisible? An Audit of CanMEDS Roles in Entrustable Professional Activities
Authors: LoGiudice Andrew B. , Sibbald Matthew , Monteiro Sandra , Sherbino Jonathan , Keuhl Amy , Norman Geoffrey R. , Chan Teresa M.
Published: May 2022

Purpose

Postgraduate medical education in Canada has quickly transformed to a competency-based model featuring new entrustable professional activities (EPAs) and associated milestones. It remains unclear, however, how these milestones are distributed between the central medical expert role and 6 intrinsic roles of the larger CanMEDS competency framework. A document review was thus conducted to measure how many EPA milestones are classified under each CanMEDS role, focusing on the overall balance between representation of intrinsic roles and that of medical expert.

Method

Data were extracted from the EPA guides of 40 Canadian specialties in 2021 to measure the percentage of milestones formally linked to each role. Subsequent analyses explored for differences when milestones were separated by stage of postgraduate training, weighted by an EPA’s minimum number of observations, or sorted by surgical and medical specialties.

Results

Approximately half of all EPA milestones (mean = 48.6%; 95% confidence interval [CI] = 45.9, 51.3) were classified under intrinsic roles overall. However, representation of the health advocate role was consistently low (mean = 2.95%; 95% CI = 2.49, 3.41), and some intrinsic roles—mainly leader, scholar, and professional—were more heavily concentrated in the final stage of postgraduate training. These findings held true under all conditions examined.

Conclusions

The observed distribution of roles in EPA milestones fits with high-level descriptions of CanMEDS in that intrinsic roles are viewed as inextricably linked to medical expertise, implying both are equally important to cultivate through curricula. Yet a fine-grained analysis suggests that a low prevalence or late emphasis of some intrinsic roles may hinder how they are taught or assessed. Future work must explore whether the quantity or timing of milestones shapes the perceived value of each role, and other factors determining the optimal distribution of roles throughout training.
Sensory neuron–expressed TRPC3 mediates acute and chronic itch
Authors: Liu Yan , Liu Yutong , Limjunyawong Nathachit , Narang Claire , Jamaldeen Hanna , Yu Shimeng , Patiram Shivanie , Nie Hong , Caterina Michael J. , Dong Xinzhong , Qu Lintao
Published: May 2022

Chronic pruritus is a prominent symptom of allergic contact dermatitis (ACD) and represents a huge unmet health problem. However, its underlying cellular and molecular mechanisms remain largely unexplored. TRPC3 is highly expressed in primary sensory neurons and has been implicated in peripheral sensitization induced by proinflammatory mediators. Yet, the role of TRPC3 in acute and chronic itch is still not well defined. Here, we show that, among mouse trigeminal ganglion (TG) neurons, Trpc3 mRNA is predominantly expressed in nonpeptidergic small diameter TG neurons of mice. Moreover, Trpc3 mRNA signal was present in most presumptively itch sensing neurons. TRPC3 agonism induced TG neuronal activation and acute nonhistaminergic itch-like and pain-like behaviors in naive mice. In addition, genetic deletion of Trpc3 attenuated acute itch evoked by certain common nonhistaminergic pruritogens, including endothelin-1 and SLIGRL-NH2. In a murine model of contact hypersensitivity (CHS), the Trpc3 mRNA expression level and function were upregulated in the TG after CHS. Pharmacological inhibition and global knockout of Trpc3 significantly alleviated spontaneous scratching behaviors without affecting concurrent cutaneous inflammation in the CHS model. Furthermore, conditional deletion of Trpc3 in primary sensory neurons but not in keratinocytes produced similar antipruritic effects in this model. These findings suggest that TRPC3 expressed in primary sensory neurons may contribute to acute and chronic itch through a histamine independent mechanism and that targeting neuronal TRPC3 might benefit the treatment of chronic itch associated with ACD and other inflammatory skin disorders.
Report of the 2020 British Nuclear Medicine Society survey of nuclear medicine equipment, workforce and workload
Authors: Irwin Andy G , Turner Christine L , Redman Stewart
Published: May 2022

The British Nuclear Medicine Society (BNMS) survey represents the only resource that brings together detailed information on equipment, workforce and workload from the practice of nuclear medicine in the UK. This article is a report of the most recent BNMS survey which was collected during 2019 and 2020. The survey used two methods to collect data: for equipment and workforce, participants created or updated existing online records; for workload information, respondees were asked to submit 12 months of data from local radiology information systems. Following the survey, the BNMS database contained a total of 191 sites (63% of known sites) having either equipment or workforce data or both. In total 39 centres provided workload data which included over 175 000 examinations. A combination of automated tools and visual inspection were used to clean, sort and validate submitted data into formats that allowed further analysis and extraction of useful parameters. Results are presented that the authors believe may be useful for nuclear medicine professionals and other stakeholders. Potential applications include benchmarking for service review and equipment replacement/updating. The survey represents a valuable resource that might be used by the BNMS secretariat to respond to specific queries from BNMS members.
Lived Travel Nurse and Permanent Staff Nurse Pandemic Work Experiences as Influencers of Motivation, Happiness, Stress, and Career Decisions
Authors: Hansen April , Tuttas Carol
Published: May 2022

Researchers explored travel nurses' and permanent staff nurses' COVID-19 pandemic work experiences, seeking to understand, “How do these experiences influence nurses' motivation, happiness, stress, and career decisions?” The COVID-19 pandemic took a heavy physical and psychological toll on health care providers. Demand outweighed resources as nurses accepted the monumental task of caring for communities affected by the catastrophe. We aimed to gain insight into nurses' lived pandemic experiences in the United States, while exploring the impact of these experiences on their motives to remain in current positions or alter their career paths. In this descriptive, phenomenological study, interview data collected from 30 nurses were analyzed using qualitative content analysis. Physical and emotional trauma experienced during the early and peak months of the pandemic led nurses to evaluate their current work arrangements and to ponder alternatives. Our results suggest that pandemic work environments contributed to a change in nursing workforce distribution and exacerbated widening nurse shortage gaps. A call to action bids leaders to institute retention measures based on factors influencing nurses' career trajectory decisions in the current environment. Our findings led to recommendations for leadership approaches to promote nurses' emotional healing and mental wellness.
Preterm Labor: A Comprehensive Review of Guidelines on Diagnosis, Management, Prediction and Prevention
Authors: Giouleka Sonia , Tsakiridis Ioannis , Kostakis Nikolaos , Koutsouki Georgia , Kalogiannidis Ioannis , Mamopoulos Apostolos , Athanasiadis Apostolos , Dagklis Themistoklis
Published: May 2022

Importance

Preterm labor (PTL) is one of the most common and serious pregnancy complications associated with significant perinatal morbidity and mortality, as well as long-term neurologic impairment in the offspring.

Objective

The aim of this study was to review and compare the most recently published major guidelines on diagnosis, management, prediction, and prevention of this severe complication of pregnancy.

Evidence Acquisition

A descriptive review of guidelines from the National Institute for Health and Care Excellence (NICE), the World Health Organization, the American College of Obstetricians and Gynecologists, the New South Wales Government, and the European Association of Perinatal Medicine (EAPM) on PTL was carried out.

Results

There is a consensus among the reviewed guidelines that the diagnosis of PTL is based on clinical criteria, physical examination, measurement of cervical length (CL) with transvaginal ultrasound (TVUS) and use of biomarkers, although there is disagreement on the first-line diagnostic test. The NICE and the EAPM are in favor of TVUS CL measurement, whereas the New South Wales Government mentions that fetal fibronectin testing is the mainstay for PTL diagnosis. Moreover, there is consistency among the guidelines regarding the importance of treating PTL up to 34 weeks of gestation, to delay delivery for 48 hours, for the administration of antenatal corticosteroids, magnesium sulfate, and in utero transfer to higher care facility, although several discrepancies exist regarding the tocolytic drugs of choice and the administration of corticosteroids and magnesium sulfate after 34 and 30 gestational weeks, respectively. Routine cesarean delivery in case of PTL is unanimously not recommended. Finally, the NICE, the American College of Obstetricians and Gynecologists, and the EAPM highlight the significance of screening for PTL by TVUS CL measurement between 16 and 24 weeks of gestation and suggest the use of either vaginal progesterone or cervical cerclage for the prevention of PTL, based on specific indications. Cervical pessary is not recommended as a preventive measure.

Conclusions

Preterm labor is a significant contributor of perinatal morbidity and mortality with a substantial impact on health care systems. Thus, it seems of paramount importance to develop consistent international practice protocols for timely diagnosis and effective management of this major obstetric complication and subsequently improve pregnancy outcomes.

Target Audience

Obstetricians and gynecologists, family physicians.

Learning Objectives

After participating in this activity, the physician should be better able to identify the symptoms of established preterm labor; describe the recommended management strategies for preterm labor; and explain the prediction and prevention methods for the reduction of preterm labor rates.
Fosfomycin Prevents Intravenous Antibiotic Therapy in Women With Recurrent Urinary Tract Infections: A Retrospective Review
Authors: Carroll Timothy F. , Christie Alana L. , Prokesch Bonnie C. , Zimmern Philippe E.
Published: May 2022

(Abstracted from Female Pelvic Med Reconstr Surg 2022;28:109–114)

Recurrent urinary tract infections (rUTIs) are common in menopausal woman. Reasons for rUTIs in this population include factors related to aging: hormonal changes, decreased immunity, and urinary incontinence.