Effects of hemodialysis adequacy on chronic kidney disease complications using latent class trajectory modeling: a real-world study based on long-term observation of Kt/V.

Introduction: Previous studies on hemodialysis adequacy primarily focused on the association between Kt/V and survival, and low Kt/V is associated with increased mortality. There is a paucity of research on the correlation between Kt/V and chronic kidney disease (CKD) complications. Methods: The retrospective study was conducted in the blood purification center of a tertiary hospital in China from July 2020 to September 2022. It aimed to analyze the association between latent Kt/V trajectory categories and CKD complications (hypertension, anemia, mineral and bone disorder) and inflammatory markers. The latent class trajectory model was established to describe the different patterns of Kt/V changes over the observation period. Results: During the 2-year study period, 93 patients on thrice-weekly hemodialysis with residual kidney function <2 mL/min were included. In the 3-class Kt/V trajectory model, 21 patients were in class 1 with a Kt/V trajectory that declined from a higher to lower levels (from >1.6 to <1.4), 59 patients were in class 2 with Kt/V consistently in a relatively low range (around 1.4), and 13 patients were in class 3 with Kt/V stabilized around 1.6. No significant difference in CKD complications or inflammation markers was observed among the three Kt/V trajectories. Conclusion: Under the premise of adequate Kt/V, neither a stable higher Kt/V nor a declined Kt/V significantly influenced CKD complications or inflammatory markers.

Research progress on measurement methods and evaluation of the hemodialysis adequacy index Kt/V.

The most common form of replacement therapy for end-stage renal disease (ESRD) is hemodialysis, and the adequacy of hemodialysis is strongly associated with the quality of life and long-term survival of patients. Kt/V is currently one of the most important indicators for evaluating the adequacy of hemodialysis. There are many methods for measuring Kt/V, such as blood collection and measurement, dialysate measurement, bioresistive resistance, WinNonlin software analysis, and artificial intelligence. There are different views on the importance of Kt/V as an indicator of the adequacy of hemodialysis. This article provides a literature review of the various methods of measuring Kt/V and on different perspectives on Kt/V as an evaluation of hemodialysis adequacy.

How low can we go with the dialysate flow? A retrospective study on the safety and adequacy of a water-saving dialysis prescription.

Background: Green nephrology encompasses all initiatives in kidney care that have a positive impact on climate and environment. To prepare the dialysate, at least 120 L of water are needed for one 4-h session with a dialysate flow (Qd) set at 500 mL/min. A lower dialysate flow rate is associated with a significant reduction in the amount of water used. The aim of this study was to check whether change of Qd from 500 mL/min to 300 mL/min has a significant impact on dialysis adequacy. Methods: The study was a retrospective analysis. Due to administrative issues, a satellite dialysis center reduced their dialysate flow to 300 mL/min for a month. The center then increased Qd to 500 mL/min again. We analyzed laboratory data from 3 months before dialysate flow reduction, in the month with Qd reduced to 300 mL/min, and from 3 months thereafter with Qd set at 500 mL/min. Results: Twenty-four people were included in the final analysis. There were no significant changes in urea reduction ratio caused by lower rate of Qd [64.50 (61.75-71.00) vs 67.00 (63.00-72.25) vs 69.00 (63.75-72.25), analysis of variance F(2,46) = 0.71, P = .50]. Similarly, hemodialysis adequacy expressed by Kt/V did not differ at any Qd [1.23 (1.12-1.41) vs 1.25 (1.18-1.40) vs 1.35 (1.19-1.48), ANOVA F(2,46) = 2.51, P = .09]. There was a small but statistically significant increase in mean predialysis potassium with lower Qd [potassium = 5.18 (95% confidence interval, 95% CI, 4.96-5.44) vs 5.46 (95% CI 5.23-5.69) vs 5.23 (95% CI 4.99-5.47) mmol/L at Qd = 500, 300 and 500 mL/min, respectively, P = .039]. Conclusion: Reduction in dialysate flow rate to 300 mL/min seems safe and does not cause any short-term negative effects in this small study. Thus, we might be able to achieve a similar therapeutic effect while saving water consumption. Larger, long-term studies incorporating patient-reported outcome measures are needed to confirm the efficacy of this approach.

Optimization of Bangladesh and Malaysian genotype recombinant reporter Nipah viruses for in vitro antiviral screening and in vivo disease modeling.

Nipah virus (NiV) causes near-annual outbreaks of fatal encephalitis and respiratory disease in South Asia with a high mortality rate (∼70%). Since there are no approved therapeutics for NiV disease in humans, the WHO has designated NiV and henipaviral diseases priority pathogens for research and development. We generated a new recombinant green fluorescent reporter NiV of the circulating Bangladesh genotype (rNiV-B-ZsG) and optimized it alongside our previously generated Malaysian genotype reporter counterpart (rNiV-M-ZsG) for antiviral screening in primary-like human respiratory cell types. Validating our platform for rNiV-B-ZsG with a synthetic compound library directed against viral RNA-dependent RNA polymerases, we identified a hit compound and confirmed its sub-micromolar activity against wild-type NiV, green fluorescent reporter, and the newly constructed bioluminescent red fluorescent double reporter (rNiV-B-BREP) NiV. We furthermore demonstrated that rNiV-B-ZsG and rNiV-B-BREP viruses showed pathogenicity comparable to wild-type NiV-B in the Syrian golden hamster model of disease, supporting additional use of these tools for both pathogenesis and advanced pre-clinical studies in vivo.

Impact of tropical cyclone Biparjoy on oceanic parameters in the Arabian Sea.

Climate change is expected to intensify tropical cyclones (TCs), requiring a deeper understanding of their ecosystem impacts. This study investigated TC Biparjoy impact on parameters from June 6 to 19, 2023, using satellite and vertical profiles. Initially, Chlorophyll-a levels remained steady but surged above 4 mg/m3 after the high-intensity phase, indicating increased phytoplankton biomass. Sea surface temperature (SST) initially exceeded 32 °C, favoring cyclone intensification, but dropped below 26 °C post-high-intensity phase due to mixing and upwelling of cooler waters. The SST gradient exceeded 0.15 °C/km post-cyclone. Elevated sea surface height around 0.5 m offshore and over 1 m along the coast was recorded. Wind stress values exceeding 0.4 N/m3 were observed during the high-intensity phase. Vertical profile showed uplifted low-temperature, nutrient-rich waters, enhancing phytoplankton productivity, supported by increased nitrate (>10 mmol/m3) and phosphate (>1.2 mmol/m3) levels. Additionally, slight increase in DIC, and pH during the cyclone period suggested changes in biogeochemical processes.

The effectiveness of a knowledge translation intervention on the implementation of NEWS2 in nursing homes, a pragmatic cluster RCT.

BACKGROUND: Improving the uptake of relevant and reliable research is an important priority in long-term care to achieve sustainable and high-quality services for the increasingly older population. AIM: The purpose was to assess the effectiveness of a tailored, adaptive and a multifaceted KT capacity program, relative to usual practice, on the implementation of National Early Warning Score 2 (NEWS2). METHODS: This study was carried out as a pragmatic cluster-randomized controlled trial. The capacity program consisted of an educational part to address implementation capacity gaps and a facilitation-upon-implementation part to address a relevant knowledge gap in nursing homes. A collective decision was made to address the challenge of early detection of clinical deterioration among nursing home residents, by implementing the (NEWS2) as clinical innovation. Public nursing homes in a Norwegian municipality (n = 21) with a total of 1 466 beds were eligible for inclusion. The study-period spanned over a 22-month period, including a 12-month follow-up. Data was extracted from the Electronic Patient Journal system and analyzed using multilevel growth model analysis. RESULTS: The intervention had a large effect on the use of NEWS2 among care staff in intervention nursing homes, compared to the control group (standardized mean difference, d = 2.42). During the final month of the implementation period, residents in the intervention group was assessed with NEWS2 1.44 times (95% CI: 1.23, 1.64) per month, which is almost four times more often than in the control group (mean = 0.38, 95% CI: 0.19, 0.57). During the follow-up period, the effect of the intervention was not only sustained in the intervention group but there was a substantial increase in the use of NEWS2 in both the intervention (mean = 1.75, 95% CI: 1.55, 1.96) and control groups (mean = 1.45, 95% CI: 1.27, 1.65). CONCLUSIONS: This tailored implementation strategy had a large effect on the use of NEWS2 among care staff, demonstrating that integrated knowledge translation strategies can be a promising strategy to achieve evidence-based care in the nursing home sector. TRIAL REGISTRATION: ISRCTN12437773 . Registered 19/3 2020, retrospectively.

The development and validation of the "Kuesioner Tema Proyek Penguatan Profil Pelajar Pancasila" (KT P5): A new tool for strengthening the Pancasila Student Profile in Indonesian pioneer schools.

The Pancasila Student Profile Strengthening Project/Projek Penguatan Profil Pelajar Pancasila (P5), initiated by the Indonesian government, aims to cultivate an independent curriculum in pioneer schools, presenting a challenge in selecting the most appropriate theme from the available seven: Nurture Their Spirit and Body (NS), Local Wisdom (LW), Engineering and Technology (ET), Voice of Democracy (VD), Sustainable Lifestyle (SL), Unity in Diversity/Bhinneka Tunggal Ika (UD), and Entrepreneurship (EP). This study developed and validated a P5 Theme Questionnaire/Kuesioner Tema (KT) to ascertain the priority theme aligning with student needs. Engaging ten pioneer junior high schools, the research surveyed 524 students. Exploratory Factor Analysis (EFA) revealed a seven-factor theme model with 34 items, each demonstrating an average factor loading of greater than 0.7. Confirmatory Factor Analysis (CFA) corroborated the model's robustness (RMSEA = 0.025, CFI = 0.984, GFI = 0.991) and high reliability (Coefficient ω = 0.945, Coefficient α = 0.825). Gender-based preferences emerged, with male students favoring Unity in Diversity, Local Wisdom, and Nurture Their Spirit and Body, while female students preferred Local Wisdom, Voice of Democracy, and Sustainable Lifestyle. This research aimed to evaluate the EFA results for each P5 theme, assess the CFA model fitness, and identify student preferences for themes. Ultimately, the "Kuesioner Tema Proyek Penguatan Profil Pelajar Pancasila" (KT P5) serves as a practical and reliable instrument for identifying preferred P5 themes in pioneer schools, facilitating effective implementation of the P5 project.

Unraveling the effects of acrylonitrile butadiene styrene (ABS) microplastic ageing on the sorption and toxicity of ionic liquids with 2,4-D and glyphosate herbicides.

Microplastics represent a novel category of environmental pollutants, and understanding their interactions with typical xenobiotics is crucial. In this study, we investigated the impact of ionic liquids (ILs) containing herbicidal anions, namely glyphosate [Glyph] and 2,4-dichlorophenoxyacetate [2,4-D], and the surfactant cation - dodecyltrimethylammonium [C12TMA] on acrylonitrile butadiene styrene (ABS) microplastics. The aim of the study was to assess the sorption capacity of microplastics that were present in both untreated and aged form using standard and modified Fenton methods. In addition, impact on toxicity and stress adaptation of the model soil bacterium Pseudomonas putida KT2440 was measured. Upon ageing, ABS microplastics underwent a fivefold increase in BET surface area and total pore volume (from 0.001 to 0.004 cm3/g) which lead to a dramatic increase in adsorption of the cations on ABS microplastics from 40 to 45% for virgin ABS to 75-80% for aged ABS. Toxicity was mainly attributed to hydrophobic cations in ILs (EC50 ∼ 60-65 mg/dm3), which was also mitigated by sorption on ABS. Furthermore, both cations and anions behaved similarly across different ILs, corresponding chlorides, and substrates used in the ILs synthesis. These findings highlight microplastics potential as hazardous sorbents, contributing to the accumulation of xenobiotics in the environment.

Long-term isoagglutinin monitoring after ABO-incompatible kidney transplantation.

OBJECTIVES: This study aimed to evaluate whether a 2-week period of daily isoagglutinin titer testing after ABO-incompatible kidney transplantation (ABOi-KT) is sufficient to ensure successful engraftment and to advocate for an extension of the monitoring duration in specific situations. METHODS: We reviewed patients from January 2022 to December 2023 at Asan Medical Center who underwent therapeutic plasma exchange (TPE) due to elevated ABO antibody titers and suspected acute antibody-mediated rejection (AMR) after ABOi-KT. Data collected included pre- and posttransplantation laboratory results, clinical and procedural information, imaging studies, and needle biopsy results of the renal graft. RESULTS: We encountered 3 cases of acute AMR 2 weeks after transplantation. All cases exhibited simultaneous increases in anti-ABO antibody isoagglutinin titers, creatinine, and C-reactive protein levels. Clinical signs, including fever, suggested possible infection, and renal graft biopsy, confirmed AMR in all cases. Two cases underwent graftectomy, while the third recovered renal function after conservative treatment, including TPE. CONCLUSIONS: Our findings suggest that a 2-week monitoring period for isoagglutinin titers after ABOi-KT may not be sufficient to detect late AMR. Extending the monitoring duration and considering lifelong fresh-frozen plasma transfusion with graft-compatible blood types, along with periodic isoagglutinin titer testing in cases of suspected AMR, may improve long-term graft outcomes.

Systems biology of electrogenic Pseudomonas putida - multi-omics insights and metabolic engineering for enhanced 2-ketogluconate production.

BACKGROUND: Pseudomonas putida KT2440 has emerged as a promising host for industrial bioproduction. However, its strictly aerobic nature limits the scope of applications. Remarkably, this microbe exhibits high bioconversion efficiency when cultured in an anoxic bio-electrochemical system (BES), where the anode serves as the terminal electron acceptor instead of oxygen. This environment facilitates the synthesis of commercially attractive chemicals, including 2-ketogluconate (2KG). To better understand this interesting electrogenic phenotype, we studied the BES-cultured strain on a systems level through multi-omics analysis. Inspired by our findings, we constructed novel mutants aimed at improving 2KG production. RESULTS: When incubated on glucose, P. putida KT2440 did not grow but produced significant amounts of 2KG, along with minor amounts of gluconate, acetate, pyruvate, succinate, and lactate. 13C tracer studies demonstrated that these products are partially derived from biomass carbon, involving proteins and lipids. Over time, the cells exhibited global changes on both the transcriptomic and proteomic levels, including the shutdown of translation and cell motility, likely to conserve energy. These adaptations enabled the cells to maintain significant metabolic activity for several weeks. Acetate formation was shown to contribute to energy supply. Mutants deficient in acetate production demonstrated superior 2KG production in terms of titer, yield, and productivity. The ∆aldBI ∆aldBII double deletion mutant performed best, accumulating 2KG at twice the rate of the wild type and with an increased yield (0.96 mol/mol). CONCLUSIONS: By integrating transcriptomic, proteomic, and metabolomic analyses, this work provides the first systems biology insight into the electrogenic phenotype of P. putida KT2440. Adaptation to anoxic-electrogenic conditions involved coordinated changes in energy metabolism, enabling cells to sustain metabolic activity for extended periods. The metabolically engineered mutants are promising for enhanced 2KG production under these conditions. The attenuation of acetate synthesis represents the first systems biology-informed metabolic engineering strategy for enhanced 2KG production in P. putida. This non-growth anoxic-electrogenic mode expands our understanding of the interplay between growth, glucose phosphorylation, and glucose oxidation into gluconate and 2KG in P. putida.

Prevalence of adrenal rest tumors and course of gonadal dysfunction in a clinical sample of men with congenital adrenal hyperplasia: a longitudinal analysis over 10 years.

BACKGROUND: Subfertility is prevalent in men with classic 21-hydroxylase deficiency (21OHD). We sought to characterize the long-term evolution of their gonadal function. METHODS: Retrospective longitudinal single-center study in 27 men (11 with testicular adrenal rest tissue [TART]), median observation period 12 years, testosterone (T), 11-oxygenated androgens, gonadotropins, and inhibin B measurement at each time point. RESULTS: T concentrations were below the normal range (n.s.) in 43.2% (no TART) and 54.6% (TART) per patient. After accounting for body mass index, sex hormone-binding globulin, and age, men with TART exhibited higher T (14.0 ± 0.80 nmol/L) than those without (11.9 ± 0.71 nmol/L). During the observation period, T levels rose in both groups but more in men with TART (from 10.1 ± 1.1 to 17.3 ± 1.9 nmol/L vs 10.3 ± 1.0 to 12.8 ± 1.9 nmol/L); this was accompanied by rising luteinizing hormone and diminishing hydrocortisone equivalent dosages (TART: from 38.1 ± 3.2 to 35.1 ± 1.8 mg/d; vs no TART: 28.8 ± 2.7 to 28.1 ± 1.6 mg/d) without correlation with any markers of adrenal androgen control. Inhibin B declined in men with large TART over time while TART status remained stable. CONCLUSION: T levels below the normal range are frequent in men with 21OHD, regardless of TART, but change little over time. Besides adrenal androgen control gonadal axis suppression from supraphysiological glucocorticoid dosages needs to be considered. While our results do not endorse regular screening for alterations in TART status among adults, Sertoli cell function should be monitored in men with large TART.

Anterior cruciate ligament reconstruction in the elderly: 5-Year follow-up study.

BACKGROUND: Older adults remain active for longer and continue sports and activities that require rotation on one leg later in life. The rate of anterior cruciate ligament (ACL) tears is therefore increasing in those over 40 years old, with an associated increase in the rate of surgical reconstruction (ACLR), but there is limited literature on its effectiveness. Our aim was to compare the outcomes of elderly patients who have undergone ACLR with those of a younger group of patients. MATERIALS AND METHODS: Patients who underwent ACLR with bone-patella tendon-bone grafting (BPTB) at a level I trauma center between 2015 and 2017 were included in the study with a 5-year follow-up. Patients were divided into 4 groups: below 40 years, 40-49 years, 50-59 years and over 60 years. The graft function was evaluated by the International Knee Documentation Committee (IKDC) Objective Score, the anteroposterior (AP) displacement was measured by arthrometer (KT-1000; MEDMetric) and the Lysholm scale was used for subjective evaluation. RESULTS: 195 patients were included in the final analysis. The IKDC score showed significantly poorer scores in the 50-59 years and over 60 years group than in the younger groups, however in 83 % and 66 % of cases reached normal or nearly normal grades, respectively. A significant difference was found in the knee AP displacement (measured in mm) between the below 40 years group and 50-59 years as well as over 60 years old groups; however, the number of graft failure (laxity >5 mm) and elongation (>3 mm) did not increased in these senior groups. The patient-reported Lysholm scores in the 40-49 years, 50-59 years and 60 years groups was lower than in the below 40 years group, but the average score was "good". CONCLUSIONS: The long-term results of ACL reconstruction in older athletes are comparable to those of younger patients, both in terms of knee function and patient satisfaction. Furthermore, there is no difference in outcomes for older patients over the age of 40 compared to those in their 50 s or even 60 s. There is still insufficient published evidence to define an upper age limit for ACL reconstruction in older athletes.

Comparison of hemodialysis urea clearance using spent dialysate and Kt/Vurea equations.

INTRODUCTION: Dialysis adequacy is traditionally calculated from pre- and post-hemodialysis session serum urea concentrations and expressed as the urea reduction ratio, or Kt/Vurea. However, with increasing hemodiafiltration usage, we wished to determine whether there were any differences between standard Kt/Vurea equations and directly measured spent dialysate urea clearance. METHODS: Urea clearance was measured from collected effluent dialysate and compared with various other methods of Kt/Vurea calculation, including change in total body urea from measuring pre- and post-total body water with bioimpedance and the Watson equation, by standard Kt/V equations, and online clearance measurements using effective ionic dialysance (OLC). RESULTS: We compared urea clearance in 41 patients, 56.1% male, mean age 69.3 ± 12.6 years with 87.8% treated by hemodiafiltration. Reduction in total body urea was greater when estimating changes in total body urea, compared to measured dialysate losses of 58.4% (48.5-67.6) vs 71.6% (62.1-78), p < 0.01. Sessional urea clearance (Kt/Vurea) was greater using the online Solute-Solver program compared to OLC, median 1.45(1.13-1.75) vs 1.2 (0.93-1.4), and 2nd generation Kt/V equations 1.3 (1.02-1.66), p < 0.01, but not different from estimated total body urea clearance 1.36 (1.15-1.73) and dialysate clearance 1.36 (1.07-1.76). The mean bias compared to the Solute-Solver program was greatest with OLC (-0.25), compared to second-generation equations (-0.02), estimated total body clearance (-0.02) and measured dialysate clearance (-0.01). CONCLUSION: This study demonstrated that the result from equations estimating urea clearance indirectly from pre- and postblood samples from hemo- and hemodiafiltration treatments was highly correlated with direct measurements of dialysate urea clearance.

SlCIPK9 regulates pollen tube elongation in tomato plants via a K+-independent mechanism.

Potassium (K+) is an essential macronutrient which contributes to osmotic- and turgor-related processes in plants. Calcineurin-B like Interacting Protein Kinases (CIPKs) play crucial roles in plants under low-K+ supply since they activate root K+ uptake transport systems such as AKT1 and AtHAK5. In Arabidopsis, AtCIPK9 is important for low-K+ tolerance since atcipk9 plants exhibited poor growth and leaf chlorosis when K+ was scarce. Part of these phenotypes could be ascribed to the activation of AtHAK5 by AtCIPK9. It has been reported that important differences exist between Arabidopsis and other plant species such as tomato with respect to the regulation of K+ uptake systems. Thus, our aim was to evaluate the contribution of SlCIPK9, the homologous protein of AtCIPK9 in tomato, to K+ nutrition. Unexpectedly, phenotyping experiments carried out with slcipk9 loss-of-function mutants revealed that SlCIPK9 did not play a clear role in tomato K+ homeostasis. By contrast, it was found that SlCIPK9 contributed to pollen tube elongation, but not to pollen germination, via a K+-independent mechanism. Therefore, our results highlight the remarkable differences that exist in Ca2+ signaling pathways between plant species and encourage the realization of more comparative studies as the one presented here.

Optimized CRISPR Interference System for Investigating Pseudomonas alloputida Genes Involved in Rhizosphere Microbiome Assembly.

Pseudomonas alloputida KT2440 (formerly P. putida) has become both a well-known chassis organism for synthetic biology and a model organism for rhizosphere colonization. Here, we describe a CRISPR interference (CRISPRi) system in KT2440 for exploring microbe-microbe interactions in the rhizosphere and for use in industrial systems. Our CRISPRi system features three different promoter systems (XylS/Pm, LacI/Plac, and AraC/PBAD) and a dCas9 codon-optimized for Pseudomonads, all located on a mini-Tn7-based transposon that inserts into a neutral site in the genome. It also includes a suite of pSEVA-derived sgRNA expression vectors, where the expression is driven by synthetic promoters varying in strength. We compare the three promoter systems in terms of how well they can precisely modulate gene expression, and we discuss the impact of environmental factors, such as media choice, on the success of CRISPRi. We demonstrate that CRISPRi is functional in bacteria colonizing the rhizosphere, with repression of essential genes leading to a 10-100-fold reduction in P. alloputida cells per root. Finally, we show that CRISPRi can be used to modulate microbe-microbe interactions. When the gene pvdH is repressed and P. alloputida is unable to produce pyoverdine, it loses its ability to inhibit other microbes in vitro. Moreover, our design is amendable for future CRISPRi-seq studies and in multispecies microbial communities, with the different promoter systems providing a means to control the level of gene expression in many different environments.

The impact of dialysate flow rate on haemodialysis adequacy: a systematic review and meta-analysis.

Background: Patients with kidney failure treated with maintenance haemodialysis (HD) require appropriate small molecule clearance. Historically, a component of measuring 'dialysis adequacy' has been quantified using urea kinetic modelling that is dependent on the HD prescription. However, the impact of dialysate flow rate on urea clearance remains poorly described in vivo and its influence on other patient-important outcomes of adequacy is uncertain. Methods: We searched Embase, MEDLINE and the Cochrane Library from inception until April 2022 for randomized controlled trials and observational trials comparing a higher dialysate flow rate (800 ml/min) and lower dialysate flow rate (300 ml/min) with a standard dialysis flow rate (500 ml/min) in adults (age ≥18 years) treated with maintenance HD (>90 consecutive days). We conducted a random effects meta-analysis to estimate the pooled mean difference in dialysis adequacy as measured by Kt/V or urea reduction ratio (URR). Results: A total of 3118 studies were identified. Of those, nine met eligibility criteria and four were included in the meta-analysis. A higher dialysate flow rate (800 ml/min) increased single-pool Kt/V by 0.08 [95% confidence interval (CI) 0.05-0.10, P < .00001] and URR by 3.38 (95% CI 1.97-4.78, P < .00001) compared with a dialysate flow rate of 500 ml/min. Clinically relevant outcomes including symptoms, cognition, physical function and mortality were lacking and studies were generally at a moderate risk of bias due to issues with randomization sequence generation, allocation concealment and blinding. Conclusion: A higher dialysate flow increased urea-based markers of dialysis adequacy. Additional high-quality research is needed to determine the clinical, economic and environmental impacts of higher dialysate flow rates.

Circulating adrenal and gonadal steroid hormones heterogeneity in active young males and the contribution of 11-oxy androgens.

The classical androgens, testosterone and dihydrotestosterone, together with dehydroepiandrosterone, the precusrsor to all androgens, are generally included in diagnostic steroid evaluations of androgen excess and deficiency disorders and monitored in androgen replacement and androgen suppressive therapies. The C11-oxy androgens also contribute to androgen excess disorders and are still often excluded from clinical and research-based steroids analysis. The contribution of the C11-oxy androgens to the androgen pool has not been considered in androgen deficiency. An exploratory investigation into circulating adrenal and gonadal steroid hormones in men was undertaken as neither the classical androgens nor the C11-oxy androgens have been evaluated in the context of concurrent measurement of all adrenal steroid hormones. Serum androgens, mineralocorticoids, glucocorticoids, progesterones and androgens were assessed in 70 healthy young men using ultra high performance supercritical fluid chromatography and tandem mass spectrometry. Testosterone, 24.5 nmol/L was the most prominent androgen detected in all participants while dihydrotestosterone, 1.23 nmol/L, was only detected in 25% of the participants. The 11-oxy androgens were present in most of the participants with 11-hydroxyandrostenedione, 3.37 nmol, in 98.5%, 11-ketoandrostenedione 0.764 in 77%, 11-hydroxytestosterone, 0.567 in 96% and 11-ketotestosterone: 0.440 in 63%. A third of the participants with normal testosterone and comparable 11-ketotestosterone, had significantly lower dehydroepiandrosterone (p < 0.001). In these males 11-hydroxyandrostenedione (p < 0.001), 11-ketoandrostenedione (p < 0.01) and 11-hydroxytestosterone (p < 0.006) were decreased. Glucocorticoids were also lower: cortisol (p < 0.001), corticosterone (p < 0.001), cortisone (p < 0.006) 11-dehydrocorticosterone (p < 0.001) as well as cortisol:cortisone (p < 0.001). The presence of dehydroepiandrosterone was associated with 16-hydroxyprogesterone (p < 0.001), which was also significantly lower. Adrenal and gonadal steroid analysis showed unexpected steroid heterogeneity in normal young men. Testosterone constitutes 78% of the circulating free androgens with the 11-oxy androgens abundantly present in all participants significantly contributing 22%. In addition, a subset of men were identified with low circulating dehydroepiandrosterone who showed altered adrenal steroids with decreased glucocorticoids and decreased C11-oxy androgens. Analysis of the classical and 11-oxy androgens with the additional measurement of dehydroepiandrosterone and 16-hydroxyprogesterone may allow better diagnostic accuracy in androgen excess or deficiency.

IRAK4 Is Overexpressed in Hidradenitis Suppurativa Skin and Correlates with Inflammatory Biomarkers.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease manifesting as painful dermal nodules, abscesses, and tunnels. Activation of the IL-1R/toll-like receptor pathway is strongly implicated in the pathogenesis of HS; thus, the role of a key signaling node, IRAK4, was investigated in a noninterventional study (NCT04440410) that enrolled 30 patients with HS. IRAK4 expression was evaluated in blood and lesional, perilesional, and nonlesional skin biopsies. PBMCs expressed IRAK4, with significantly higher levels in monocytes (P ≤ .0001). Ex vivo treatment of PBMCs with KT-474, a targeted degrader of IRAK4, robustly decreased IRAK4 in all immune cell types from healthy volunteers and patients with HS. Ex vivo treatment of toll-like receptor-stimulated healthy donor monocytes with KT-474 decreased IRAK4 protein levels and inhibited inflammatory cytokine production. In HS skin samples, IRAK4 protein levels were significantly higher in lesional than in nonlesional tissue (P ≤ .0001), and IRAK4-positive immune infiltrate increased with greater disease severity. Multiple inflammatory mediators were upregulated in HS lesional skin, correlating with IRAK4 overexpression. These data confirm the significance of the IL-1R/toll-like receptor pathway in the pathogenesis of HS and provide support for ongoing clinical studies evaluating KT-474 in the treatment of HS.