bluuebunny/crossref_metadata_2025_split huggingface dataset:
#2114 TIE2 activation promotes vascular protection of tubules to reduce PDGFB driven tubulointerstitial fibrosis in experimental chronic kidney disease
Authors: Pietilä Riikka , Marks Amanda , Betsholtz Christer , Jeansson Marie 
Published: May 2024

Abstract

Background and Aims
The relevance of endothelial dysfunction for tubulointerstitial fibrosis in chronic kidney disease (CKD) is poorly understood. Here, we utilize gain- and loss-of-function experiments to investigate the role of endothelial tyrosine kinase TIE2 for vascular-mediated protection in experimental CKD.

Method
TIE2 activation was achieved using a human TIE2-activating antibody (ABX), or conditional endothelial knockout of vascular endothelial protein tyrosine phosphatase (Veptp). Conditional endothelial knockout of Tie2 served as a TIE2-incompetent signalling model. CKD was induced by unilateral ureter obstruction (UUO).

Results
ABX treated and Veptp knockout mice were significantly protected from UUO-induced endothelial dysfunction, tubular injury, and tubulointerstitial fibrosis. Capillary density was preserved as well as fenestrations of peritubular capillaries. In contrast, Tie2 knockout mice had aggravated disease. Mechanistically, the link between endothelial dysfunction and tubulointerstitial fibrosis was tubular expression of PDGFB, which was reduced by ABX treatment and Veptp knockout. A role for endothelial-to-mesenchymal transition was ruled out by careful lineage tracing of endothelial cells and reporter for mesenchymal cells. UUO-induced tubulointerstitial fibrosis was reduced in Pdgfb knockout mice, supporting causality of PDGFB in mesenchymal activation and fibrosis. ABX treated and Veptp knockout mice had significantly lower UUO-induced PDGFB levels.

Conclusion
Our data supports a key role of the endothelium and TIE2 signalling in CKD. We introduce ABX as a new therapeutic approach in CKD and demonstrate the sequence of events from endothelial dysfunction to tubulointerstitial fibrosis.
#313 Enhanced urinary phosphorous reduction: comparative study of oxylanthanum carbonate and tenapanor in rat
Authors: Medicherla Satya , Reddy Guru , Gupta Pramod , Gupta Shalabh 
Published: May 2024

Abstract

Background and Aims
End-stage renal disease (ESRD) affects &gt;7 M people worldwide and ∼70% of patients with ESRD have hyperphosphatemia. Oxylanthanum carbonate (OLC) is a novel nanotechnology product that combines lanthanum, which has the highest binding capacity vs other phosphate (P) binders, with a smaller pill size that is swallowed with water vs chewed. Tenapanor is a sodium hydrogen exchanger inhibitor used to reduce serum P in adults with chronic kidney disease (CKD) on dialysis. A previous study conducted by King et al found that when administered together, tenapanor and sevelamer decreased urinary p excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels. Employing an identical study design and dosing regimen, the objective of our study was to evaluate the effects of tenapanor and OLC on P excretion.

Method
In our study, we utilized the study design and dosage regimen from King et al involving sevelamer and tenapanor. 64 male Sprague Dawley rats were fed standard chow 1 week prior to study start. On study day −1, animals were randomized into 3 study groups (n = 8): 1) vehicle, 2) tenapanor 0.15 mg/kg, 3) Vehicle + OLC 0.75%, 4) Vehicle + OLC 1.5%, 5) Vehicle + OLC 3%, 6) tenapanor 0.15 mg/kg + OLC 0.75%, 7) tenapanor 0.15 mg/kg + OLC 1.5%, and 8) tenapanor 0.15 mg/kg + OLC 3%. Vehicle and tenapanor were dosed PO twice/day whereas OLC was incorporated into the diets. 24-hour urine samples were collected using metabolic cages on day 9, 10, and 11 for urinary P measurements.

Results
Compared to vehicle alone (group 1), P reduction of tenapanor (group 2) was 8.5 mg/day (not significant), while P reduction of OLC (group 5) was 25.3 mg/day (significant). OLC had 16.8 mg/day more P reduction than tenapanor (Fig. 1).

Conclusion
OLC demonstrated 3x more effective urine P reduction vs tenapanor. Subsequent analyses will focus on examining the combination of tenapanor and OLC. Combining OLC and tenapanor utilizes 2 different mechanisms of action to manage P levels while having a low pill burden, which may lead to synergistic effects to be investigated in future studies.
#1387 Comprehensive evaluation of clinical consequences in diverse forms of fistula elevation procedure
Authors: Nanami Masayoshi , Mimura Yasuyuki , Kuma Akihiro , Hasuike Yukiko , Nakanishi Takeshi , Kuragano Takahiro 
Published: May 2024

Abstract

Background and Aims
Arteriovenous fistula (AVF) superficialization is a recommended alternative autologous vascular access (VA) in patients for whom conventional AVF creation is not possible because of insufficient forearm vessels. This procedure utilizes a deeply located vein as an outflow conduit in AVF creation and makes the vein accessible for cannulation. Tunnel transposition (TT) is employed in a standard manner as a venous superficialization technique. This is accomplished by tunneling the transected vein through a subcutaneous tunnel. However, TT is frequently associated with stenosis at the area of transposition because the transposed vein is torsed, kinked, or compressed by external tissue. Thus, TT tends to be exclusively applied to the basilic vein in the upper arm considering both the anatomic positional relation and the inherent limitations of this procedure. We recently reported that elevation transposition (ET) can serve as a practical substitute for TT (Contrib Nephrol. 2019:198:1-11). ET is a simplified minimally invasive superficialization approach in which the vein is elevated and positioned in a subcutaneous pocket immediately beneath the incision. In AVF superficialization employing ET (i.e., fistula elevation procedure [FEP]), three potential outflow veins are available in the upper arm: the cephalic, basilic, and brachial veins. This study was performed to comprehensively evaluate the clinical consequences of three valid FEP techniques to ascertain whether they are reasonable alternatives to autologous VA and which, if any, have superior performance.

Method
The demographic and outcome data of 111 patients who underwent the FEP from April 2016 to June 2023 were retrospectively collected and analyzed. The outcomes of the three fistula techniques were assessed and compared in terms of patency rates, requirements for VA intervention therapy (VAIVT), and complication rates.

Results
The mean follow-up period was 36.2 ± 20.1 (range, 1.3-80.8) months. The basilic, cephalic, and brachial vein-based FEP was performed in 63.1%, 23.4%, and 13.5% of cases, respectively. The overall cumulative primary and secondary patency rates were 76.2% and 98.2% at 1 year and 70.7% and 97.0% at 2 years, respectively. VAIVT was required in 32.4% of cases, and the patency rates at 1 and 2 years after VAIVT were 65.3% and 62.0%, respectively. There were no significant differences in these patency rates among the three FEP types. Minor complications such as lymphorrhea or epidermolysis occurred in only 4.5% of cases.

Conclusion
Our results suggest that the FEP provides three equivalently reliable options to accommodate the deeply located venous anatomy of the upper arm on individual-patient basis. The diversity of the FEP may contribute to avoiding prosthetic VA and central venous catheter-based dialysis, at least in part, by expanding the applicability of the autologous VA.
#3142 Evaluation of antipruritic effect of tacrolimus on hemodialysis patients with uremic pruritus, a double-blind, randomized, clinical trial
Authors: Roozbeh Jamshid , Masjedi Fatemeh 
Published: May 2024

Abstract

Background and Aims
Pruritus in patients undergoing hemodialysis is a highly prevalent complication that affects quality of life. Several medications are currently used for the treatment of uremic pruritus, but these are not satisfactory.
There are few studies about the beneficial effect of oral Tacrolimus on dermatologic problems such as pruritus. Considering the condition of hemodialysis in ESKD patients and the probable presence of oral Tacrolimus in their future treatment plan, this trial is designed to assess the antipruritic effect of Tacrolimus compared with placebo.

Method
This multicenter, randomized, double-blind, placebo-controlled clinical trial included 75 patients undergoing hemodialysis. The patients were randomized to a treatment group (Tacrolimus 1 mg/day) or a control group (placebo). The treatment lasted eight weeks, followed by a 2-week observational period. Visual Analogue Scale (VAS), % affected Body Surface Area (%BSA), and 12-Pruritus Severity Scale questionnaire (12-PSS) were measured before and after treatment periods. Moreover, sleep quality and the effect of sex were also evaluated.

Results
Seventy-five patients under hemodialysis (mean age of 58.18 ± 09.39 years) completed the study. Mean changes in VAS, %BSA, and 12-PSS after the interventions (Tacrolimus vs. placebo, mean ± SD) were as follows, respectively: −3.77 ± 2.13 vs. −1.07 ± 1.17, −18.97 ± 12.20 vs. 2.44 ± 3.23, and −4.67 ± 3.21 vs. −1.32 ± 2.45 (P &lt; 0.0001). An improvement in sleep quality was found in 52.6% (20/38) of patients after Tacrolimus intake (P &lt; 0.01). Overall, Tacrolimus was more effective in women than men (P &lt; 0.016).

Conclusion
Based on the preliminary results of this study, Tacrolimus can be introduced as an effective drug for the management of pruritus and can be an add-on therapy in uremic patients.
#1419 A single, easy-to-use question to assess pruritus intensity in daily dialysis practice
Authors: Mccafferty Kieran , Morin Isabelle , Menzaghi Frederique , Schaufler Thilo 
Published: May 2024

Abstract

Background and Aims
Chronic kidney disease-associated pruritus (CKD-aP) has been shown to negatively impact certain clinical outcomes and quality of life (QoL) in patients with kidney failure. However, regular screening for CKD-aP is not yet routine dialysis practice and no consensus on the preferred instrument exists. To facilitate implementation of regular screening for CKD-aP we assessed the performance of two different instruments validated in patients with CKD-aP.

Method
The Worst Itching Intensity Numerical Rating Scale (WI-NRS) asks patients to indicate the worst itch intensity in the past 24 hours (range 0 [no itch] to 10 [worst itch imaginable]). The 5-D Itch scale assesses itch-related QoL (range 5-25 where higher values indicate worse QoL) and includes one question on itch intensity over the past 2 weeks (5-D ‘degree’ domain, range 1 [not present] to 5 [unbearable]).
Both instruments were included in two phase-3 clinical trials, KALM-1 and KALM-2, that established the favourable benefit-risk profile of difelikefalin over placebo in patients on haemodialysis with moderate to severe CKD-aP. WI-NRS was collected daily during the trial and 5-D Itch at the first dialysis visit in weeks 5, 9, 11 and 13.
We assessed the correlations between both the 5-D total score and degree domain and a) the single WI-NRS measurement collected on the same day and b) the average of daily WI-NRS scores collected over the previous 2 weeks in all patients independent of treatment exposure.

Results
The two instruments demonstrated moderate to strong correlations (range 0.5635-0.7039, p &lt; 0.0001) independent of whether the total 5-D Itch score or the 5-D itch degree question were compared with a single, same-day WI-NRS measurement or with the mean WI-NRS scores over the 2-week recall period of the 5-D Itch (Table).
In addition, correlations remained consistent over time, supporting the reliability of the findings.

Conclusion
Using the WI-NRS to ask patients about their worst itch in the past 24 hours is a simple and swift approach for reliably identifying those with bothersome pruritus that also affects their itch-related QoL.
A Qualitative Study of Barriers and Motivators to Prevent Secondhand Smoke Exposure Among Pregnant Women and Children in Egypt: Identifying Appropriate Approaches for Change
Authors: Hassanein Zeinab M , Nalbant Gamze , Bogdanovica Ilze , Langley Tessa , Murray Rachael L 
Published: May 2024

Abstract

Introduction
The prevalence of daily secondhand smoke (SHS) exposure among pregnant nonsmoking women and children in Egypt is estimated to be about 50% and 55%, respectively. This study aimed to explore barriers to preventing SHS exposure among pregnant women/children and smoking in the home in Egypt.

Aims and Methods
Six focus group discussions with pregnant women or mothers of children residing in urban–rural areas (n = 61) were conducted. Data were managed and analyzed using the Framework Method.

Results
Sixty-one participants aged 18–49 were recruited. They reported being never smokers and SHS exposure for themselves and their children was mainly at home. Pregnant women or mothers had some general knowledge of the dangers of SHS, but their knowledge appeared incomplete. The most commonly reported barriers to preventing SHS exposure/adopting a smoke-free home or workplace were social acceptance of smoking and SHS exposure, masculinity and gender norms of accepting smoking among men as a normative behavior, fear among women of damaging a relationship with family or even divorce, women resigning themselves to SHS exposure, and doctors not being supportive of smoking cessation. The majority of interviewees’ families were reported to allow smoking anywhere in the home. Others implemented some measures to prevent SHS; however, these tended to be inconsistently implemented.

Conclusions
Changing the norm of accepting smoking among men as a normative behavior within Egyptian society and better enforcement of smoke-free policies, will help to protect pregnant women and children from SHS.

Implications
This study suggests promising approaches to support the promotion of smoke-free homes and the prevention of SHS exposure among pregnant women and children in public places in Egypt. Better enforcement of smoke-free policies is needed. Healthcare professionals should support smoking cessation services in primary health centers. SHS policy, practice, and research should focus on husbands/fathers as they are the main source of SHS. There is a need for denormalization of SHS exposure in Egyptian society.
Nutrigenetic and Epigenetic Mechanisms of Maternal Nutrition–Induced Glucolipid Metabolism Changes in the Offspring
Authors: Jiao Peng , Lu Huizhen , Hao Lizhuang , Degen A Allan , Cheng Jianbo , Yin Zongjun , Mao Shengyong , Xue Yanfeng 
Published: May 2024

Abstract
Maternal nutrition during pregnancy regulates the offspring’s metabolic homeostasis, including insulin sensitivity and the metabolism of glucose and lipids. The fetus undergoes a crucial period of plasticity in the uterus; metabolic changes in the fetus during pregnancy caused by maternal nutrition not only influence fetal growth and development but also have a long-term or even life-long impact for the offspring. Epigenetic modifications, such as DNA methylation, histone modification, and non-coding RNAs, play important roles in intergenerational and transgenerational effects. In this context, this narrative review comprehensively summarizes and analyzes the molecular mechanisms underlying how maternal nutrition, including a high-fat diet, polyunsaturated fatty acid diet, methyl donor nutrient supplementation, feed restriction, and protein restriction during pregnancy, impacts the genes involved in glucolipid metabolism in the liver, adipose tissue, hypothalamus, muscle, and oocytes of the offspring in terms of the epigenetic modifications. This will provide a foundation for the further exploration of nutrigenetic and epigenetic mechanisms for integrative mother–child nutrition and promotion of the offspring’s health through the regulation of maternal nutrition during pregnancy. Note: This paper is part of the Nutrition Reviews Special Collection on Precision Nutrition.
The effects of omega-3 polyunsaturated fatty acids on muscle and whole-body protein synthesis: a systematic review and meta-analysis
Authors: Therdyothin Atiporn , Prokopidis Konstantinos , Galli Francesco , Witard Oliver C , Isanejad Masoud 
Published: May 2024

Abstract

Context
Sarcopenia describes the age-related decline in skeletal muscle mass and strength that is driven, at least in part, by an imbalance between rates of muscle protein synthesis (MPS) and muscle protein breakdown. An expanding body of literature has examined the effect of omega-3 polyunsaturated fatty acid (n-3 PUFA) ingestion on MPS rates in older adults, with mixed findings.

Objective
The aim of this systematic review and meta-analysis was to investigate the effectiveness of n-3 PUFA ingestion in stimulating rates of MPS and whole-body protein synthesis in healthy adults and clinical populations.

Data Sources
Searches were conducted of the PubMed, Web of Science, Cochrane Library, and Scopus databases from inception until December 2022 for articles on randomized controlled trials comparing the effect of n-3 PUFA ingestion vs a control or placebo on rates of MPS and whole-body protein synthesis. The search yielded 302 studies, of which 8 were eligible for inclusion.

Data Extraction
The random effects inverse-variance model was used and standardized mean differences (SMDs) with 95%CIs were calculated to assess the pooled effect. Risk of bias was assessed by the Cochrane Risk-of-Bias 2 tool.

Data Analysis
The main analysis indicated no effect of n-3 PUFA supplementation on MPS rates (k = 6; SMD: 0.03; 95%CI, −0.35 to 0.40; I2 = 30%; P = .89). Subgroup analysis based on age, n-3 PUFA dose, duration of supplementation, and method used to measure fractional synthetic rate also revealed no effect of n-3 PUFA ingestion on MPS. In contrast, the main analysis demonstrated an effect of n-3 PUFA ingestion on increasing whole-body protein synthesis rates (k = 3; SMD: 0.51; 95%CI, 0.12–0.90; I2 = 0%; P = .01).

Conclusions
n-3 PUFA ingestion augments the stimulation of whole-body protein synthesis rates in healthy adults and clinical populations.

Systematic Review Registration
PROSPERO registration no. 42022366986.
Opioid metabolism and drug-drug interaction in cancer
Authors: Aapro Matti , Fogli Stefano , Morlion Bart , Danesi Romano 
Published: May 2024

Abstract
Concomitant use of multiple drugs in most patients with cancer may result in drug-drug interactions (DDIs), potentially causing serious adverse effects. These patients often experience unrelieved cancer-related pain (CRP) during and after cancer treatment, which can lead to a reduced quality of life. Opioids can be used as part of a multimodal pain management strategy when non-opioid analgesics are not providing adequate pain relief, not tolerated, or are contraindicated. However, due to their narrow therapeutic window, opioids are more susceptible to adverse events when a DDI occurs. Clinically relevant DDIs with opioids are usually pharmacokinetic, mainly occurring via metabolism by cytochrome P450 (CYP). This article aims to provide an overview of potential DDIs with opioids often used in the treatment of moderate-to-severe CRP and commonly used anticancer drugs such as chemotherapeutics, tyrosine kinase inhibitors (TKIs), or biologics. A DDI-checker tool was used to contextualize the tool-informed DDI assessment outcomes with clinical implications and practice. The findings were compared to observations from a literature search conducted in Embase and PubMed to identify clinical evidence for these potential DDIs. The limited results mainly included case studies and retrospective reviews. Some potential DDIs on the DDI-checker were aligned with literature findings, while others were contradictory. In conclusion, while DDI-checkers are useful tools in identifying potential DDIs, it is necessary to incorporate literature verification and comprehensive clinical assessment of the patient before implementing tool-informed decisions in clinical practice.
Adjuvant treatment strategy evolution and risk stratification for hormone receptor-positive, human epidermal growth factor receptor-2 negative early breast cancer in China
Authors: Fan Ying , Ji Danyang , Jiang Mingxia , Tan Yujing , Yang Yang , Li Tianyi , Ma Xiao , Xu Binghe 
Published: May 2024

Abstract

Background
Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2−) early breast cancer (EBC) with high-risk clinicopathological features face an increased risk of recurrence. This study explored the evolving treatment landscape and clinical outcomes in patients with EBC using a nationwide database.

Patients and Methods
The study cohort comprised HR+/HER2−, stages 1-3, patients with EBC who underwent surgery and received adjuvant endocrine therapy (AET) from January 2013 to March 2021. High-risk patients were defined by ≥4 positive axillary lymph nodes, or 1-3 positive lymph node(s) with at least one high-risk feature (histologic grade 3, tumor size ≥5 cm, or Ki-67 ≥20%). A low-risk cohort included patients not meeting the criteria. Survival analysis was conducted with a cutoff of September 2021.

Results
The study included 4088 eligible patients (1310 high-risk patients and 2778 low-risk patients). High-risk patients were more likely to receive adjuvant chemotherapy and radiotherapy compared to low-risk patients. From 2013 to 2021, an increasing proportion of patients received aromatase inhibitors and ovarian function suppression as part of their AET. The 2-, 5-, and 7-year invasive disease-free survival for high-risk cohort were 90.67%, 75.26%, and 57.10%, respectively, these rates were notably higher for low-risk cohort at 97.14%, 89.85%, and 84.83%. High-risk patients demonstrated a higher risk of recurrence or death compared with low-risk patients (hazard ratio, 2.38; 95% CI, 1.82-3.12).

Conclusion
In the setting of standard or even intensive AET, patients with EBC with high-risk features still present high recurrence risk, highlighting the urgent need for innovative adjuvant treatment strategies.
Cybersecurity
Authors: Miller Seumas , Bossomaier Terry 
Published: May 2024

Abstract
Cybersecurity is often defined in terms of data security. This definition is too narrow. A broader definition includes security issues, such as disinformation and incitement on social media platforms. Cyberthreats include viruses, ransomware, and so on, and cybersecurity responses are often technical in character (e.g., firewalls, encryption). However, cybersecurity is not simply a technical issue. Consider the threat of disinformation and countermeasures to it. The internet and other cybertechnologies are embedded in institutions. This is obvious in the case of internet governance bodies such as ICANN. However, this institutional landscape also includes global technology companies (e.g., Facebook), criminal organizations, and state actors and their security agencies (e.g., NSA in the US). Moreover, some state actors are engaged in cyberwar (e.g., Russia). Therefore, a key notion is that of an institution. Institutions ought to have as their raison d’être to provide collective good such as, which, in the case of institutions operating in cyberspace, means cybersecurity.
Entanglement
Authors: Schofield John 
Published: May 2024

Abstract
This chapter discusses a recurring issue and a characteristic of wicked problems: the fact they are all entangled with one another; any attempt to fix one problem can create problems elsewhere, mirroring archaeology whereby material entanglement characterizes the archaeological record. Entanglement is a central theme across many disciplines, not least quantum theory. This theoretical chapter discusses how archaeologists have engaged with entanglement and how this sits alongside other frameworks such as actor network theory. The concept of messiness, used as an alternative to wicked problems to describe entangled and intractable social and environmental issues, is discussed. Other alternative frameworks discussed include ecosystems and assemblage theory, systems thinking and complexity theory which offer different ways to conceptualize and address wicked problems thus providing an essential terminology and conceptual framework for archaeologists and heritage practitioners.