bluuebunny/crossref_metadata_2025 huggingface dataset:
#932 Obinutuzumab for the treatment of refractory PLA2R-associated membranous nephropathy: a single-center cohort study
Authors: Li Chao , Zheng Xixi , Zhang Lei , Wang Ying , Hu Rongrong , Cui Hao-Yuan , Xia Peng , Li Hang , Qin Yan , Chen Limeng , Li Xuemei , Li Xuewang
Published: May 2024

Background and Aims

The established first-line immunosuppressive treatment for membranous nephropathy, rituximab, is met with resistance in some cases of refractory disease. Obinutuzumab, a Type II humanized CD20 monoclonal antibody, has been documented in international case reports as a potential treatment for refractory membranous nephropathy, yet application in China is in its infancy. This study aims to investigate the preliminary short-term efficacy and safety profile of obinutuzumab in such challenging cases.

Method

We assessed six adult patients with PLA2R-associated membranous nephropathy unresponsive to rituximab, prednisone combined with cyclophosphamide, and calcineurin inhibitors. Obinutuzumab was administered intravenously at 1000 mg, preceded by prophylactic dexamethasone and diphenhydramine to mitigate infusion reactions. Immunological remission was defined as a reduction of anti-PLA2R antibodies to titers below 2RU/ml.

Results

Baseline characteristics at the initiation of obinutuzumab treatment included an average disease duration of 3.6 ± 2.1 years and a median patient age of 54 years, with a male predominance (3:1 ratio). Laboratory findings at baseline revealed serum albumin at 22 ± 4 g/L, serum creatinine at 133 ± 68 μmol/L, and a significant 24-hour urinary protein quantification (24 hUP) at 7.1 ± 2.9 g/d. The median baseline anti-PLA2R antibody titer was substantial at 90 (range 50-671) RU/ml. At follow-up (9.1 ± 3.7 months), immunological remission rates post-obinutuzumab at 1, 3, and 6 months were 33.3%, 50%, and 50%, respectively. By the end of the study, CD19+ B-cells were depleted (< 5 cells/μL) for an average duration of 6.8 ± 2.6 months. At this juncture, improvements were noted with increased serum albumin (33 ± 8 g/L) and decreased serum creatinine (125 ± 80 μmol/L), along with a reduction in 24 hUP to 4.7 ± 6.2 g/L. Clinical evaluations indicated two cases of complete remission and two of partial remission. In the remaining two patients, 24 hUP was halved compared to baseline. Prednisone dosage was reduced to 7 ± 7 mg/day, with a corresponding reduction in cyclosporine and tacrolimus dosages, and cessation of cyclophosphamide and Tripterygium wilfordii polyglycosides. There were no acute infusion reactions, but two patients suffered severe infections, including one fatality, related to COVID-19 during the pandemic.

Conclusion

Obinutuzumab emerges as a novel agent in the immunosuppressive armamentarium against refractory PLA2R-associated membranous nephropathy, warranting further long-term study. The enduring B-cell depletion necessitates a careful pre-treatment risk assessment for opportunistic infections, particularly during the ongoing COVID-19 pandemic.
#2367 Membranoproliferative glomerulonephritis preceding non-Hodgkin lymphoma recurrence : a case report
Authors: Mahfoudh Olfa , Awatef Azzabi , Thabet Nesrine , Dahmene Rihem , Aicha Narjes Ben , Mrabet Senda , Guedri Yosra , Fradi Asma , Sabri Ferdaws , Boukadida Raja , Sahtout Wissal , Zellama Dorsaf
Published: May 2024

Background and Aims

Glomerulonephritis (GN) have been known to be associated with both chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Membranoproliferative Glomerulonephritis (MPGN) is the most commonly reported histological diagnosis in these diseases.

Method

This report presented a rare case of membranoproliferative glomerulonephritis preceding non- Hodgkin lymphoma recurrence.

Results

In September 2023, we report the case of a 75-year-old woman with Sjögren's syndrome, systemic lupus erythematosus and hypertension history. Two years prior, she developed non Hodgkin lymphoma requiring chemotherapy with cyclophosphamide, prednisone, rituximab, and vincristine.

It has remained in remission. She was admitted to our department with peripheral edema complaint. Physical examination showed edema in the lower extremities. The blood pressure was 130/85 on her antihypertensive regimen. No lymphadenopathies were found.

She had mild proteinuria, microhematuria and reduced estimated glomerular filtration rate. The serum creatinine level was 190 µmol/l. She had 1.8 gr/day proteinuria.

Laboratory data showed decreased levels of serum C3, C4. Anti-nuclear antibody (ANA) screens were negative. The cryoglobulins test was negative. Hepatitis B, hepatitis C, and HIV serologies were negative.

Renal biopsy was performed and resulted as membranoproliferative glomerulonephritis with positive IgM immunofluorescence stain (Figs 1 and 2).

We therefore concluded to a membranoproliferative glomerulonephritis with monotypic immunoglobulin deposits.

After investigations, she got recurrent non-Hodgkin lymphoma diagnosis.

Discussion

GN may precede, coexist, or follow the diagnosis of lymphoma by several years.

The pathogenesis of paraneoplastic GN remains uncertain, although autoimmune mechanisms and T-lymphocyte dysfunction may be important in this respect.

Conclusion

Secondary membranoproliferative glomerulonephritis can be observed in non-Hodgkin lymphoma patients but there are few reports about clinical results of lymphoma treatment. There is limited information available concerning the effects of treatment of non-Hodgkin's lymphoma on the progression of non-Hodgkin's lymphoma associated membranoproliferative glomerulonephritis.
#1110 The AHR antagonist CH223191 alleviates kidney injury and renal fibrosis in adenine-induced chronic kidney disease
Authors: Li Hui , Ren Qian , Fu Ping , MA Liang
Published: May 2024

Background and Aims

The aryl hydrocarbon receptor (AhR) is a transcription factor that can be activated by a variety of endogenous and exogenous ligands, and is involved in varieties of biological processes. It has been confirmed that the expression of AhR in kidney is elevated in chronic kidney disease (CKD). However, the specific role of AhR signaling pathway in CKD and its molecular mechanism remain unclear. This study aims to investigate the role and underlying mechanism of AhR in CKD, providing potential targets for the treatment of CKD.

Method

Male C57/B6L mice were randomly divided into control group, model group and treatment group. The model group was fed 0.2% adenine diet for 14 days to establish CKD model, while the treatment group was treated with AhR antagonist CH223191. AhR agonist kynurenine and antagonist CH223191 was applied in mouse tubular epithelial (TCMK-1) cells to investigate the underlying mechanisms of AhR in vitro. The renal function, histological changes and renal fibrosis in mice were evaluated to explore the role of AhR in adenine-induced CKD. Histological changes were evaluated by PAS and MASSON stainings, immunohistochemistry and immunofluorescence. Western blot and qPCR were used to measure protein/gene transcription levels.

Results

The levels of serum creatinine (p <  0.0001) and urea nitrogen (p <  0.0001) in the model group were significantly increased, with obvious renal tubule dilation and renal fibrosis by PAS and MASSON staining. CH223191 treatment significantly reduced serum creatinine (p=0.0012) and urea nitrogen ( <  0.0001) levels in mice, and alleviated renal fibrosis histologically. Q-PCR and Western-Blot results showed that the renal expression level of AhR in the treatment group was decreased, while the expression levels of fibronectin (Fn) (p <  0.0001), α-smooth muscle actin (α-SMA) (p <  0.0001), type I collagen (p=0.0007) and transforming growth factor-β (TGF-b) (p=0.0027) were significantly decreased. In addition, the expression levels of N-GAL (p <  0.0001) and KIM-1 ( <  0.0001) molecular markers associated with kidney injury were reduced, suggesting that inhibiting AhR expression in vivo can reduce adenine-mediated kidney injury and renal fibrosis in CKD. In vitro experiments indicated that kynurenic acid could induce the expression of AhR and AhR downstream regulatory gene CYP1b1 and upregulated fibrosis-related genes in tubular epithelial cells, while CH223191 treatment downregulated the fibrosis-related genes in tubular epithelial cells.

Conclusion

AhR mediates renal injury and renal fibrosis in adenine-induced CKD mice. AhR antagonist CH223191 exerts a renal protective effect by reducing the expression of AhR in renal tubular epithelial cells, thereby alleviating renal injury and renal fibrosis.
#915 Role of VSIG4 in renal aging process
Authors: Cha Dae Ryong , Han Sang Youb , Ko You-Jin , Cha Jin Joo
Published: May 2024

Background and Aims

V-set Ig domain-containing 4 (VSIG4), known for its role in inflammation and fibrosis, is particularly interesting in the realm of chronic kidney diseases. However, its specific role in kidney aging, especially under the influence of diabetes, is not well understood. This study aims to elucidate the role of VSIG4 in the aging process of kidneys, particularly in the diabetes.

Method

This study used male db/db and db/m mice, beginning from the age of eight weeks and spanning 38 weeks. Urinary albumin and VSIG4 levels were assessed using 6-hour timed urine collections and ELISA. The intrarenal expression of VSIG4 and klotho were analyzed through qRT-PCR and Western blotting.

Results

Urinary albumin levels in db/db mice were significantly higher from 8 weeks onward compared to db/m mice. These levels increased progressively with age, peaking at 38 weeks. Similarly, urinary VSIG4 levels showed a significant initial increase in db/db mice, followed by a consistent rise with age. Interestingly, both urinary albumin and VSIG4 levels in db/m mice showed a sudden surge at 38 weeks. Notably, urinary VSIG4 levels paralleled these changes in albumin levels, with a correlation coefficient of 0.867 (p < 0.001). Intrarenal VSIG4 mRNA expression was markedly higher in diabetic mice and showed a significant increase at 16 and 38 weeks, with the 38-week levels being fivefold higher in db/m mice. The expression trends of VSIG4 protein were similar to its mRNA expression. The study also monitored intrarenal klotho expression to assess aging, which revealed a progressive decrease in both mRNA and protein levels with age.

Conclusion

This study highlights a significant upregulation of both urinary and intrarenal VSIG4 expressions in diabetic and non-diabetic mice. The strong association of urinary VSIG4 expression with albuminuria suggests its involvement in the renal aging process, potentially contributing to the pathogenesis of age-related kidney alterations.
#612 Serum citrulline level is associated with oxidative stress and chronic kidney disease progression
Authors: Korol Lesya , Stepanova Natalia , Vasylchenko Victoria
Published: May 2024

Background and Aims

Citrulline, an α-amino acid crucial for the urea cycle and nitric oxide production, plays a protective role against free radicals and is indirectly related to protein metabolism. It is synthesized in the intestine and efficiently absorbed by the proximal renal tubules, where it is converted to urea via arginine. Although citrulline has multiple physiological effects, its involvement in the progression of chronic kidney disease (CKD) has not been explored. This cross-sectional study aimed to investigate the relationship between serum citrulline levels, CKD progression, and markers of oxidative stress.

Method

A total of 135 subjects were enrolled in this cross-sectional study. This cohort included 30 relatively healthy individuals who constituted the control group and 105 CKD patients who were categorized according to their estimated glomerular filtration rate (eGFR). We measured serum citrulline concentrations along with markers of oxidative stress, including paraoxonase 1 (PON-1), myeloperoxidase (MPO), and malondialdehyde (MDA), using the spectrophotometric method.

Data were expressed as mean (M) and standard deviation (SD) or median and interquartile range [Me (Q25-Q75)] according to the data distribution and compared with the Kruskal-Wallis test. Spearmen correlation test was performed to evaluate the correlation between the studied data.

Results

Our findings revealed a significant increase in citrulline and MDA concentrations and MPO activity and a significant decrease in PON-1 in the CKD group compared with the control group. Moreover, a significant association emerged between serum citrulline levels and the severity of CKD, as determined by eGFR. Specifically, patients in advanced CKD stages exhibited elevated serum citrulline concentrations in contrast to those in earlier stages (Table 1).

Furthermore, a significant correlation was established between serum citrulline and oxidative stress markers, with higher citrulline levels positively associated with increased concentrations of MDA (r = 0.46, p = 0.002) and heightened MPO activity (r = 0.85, p  <  0.001), and demonstrating an inverse relationship with PON-1 in CKD stages 1-2 and 5 (r = -0.64, p  < 0.001 and r = -0.47, p = 0.004, respectively).

Conclusion

This cross-sectional study suggests that serum citrulline level is associated with both CKD progression and oxidative stress intensity in patients with CKD. These findings highlight the potential role of citrulline as a biomarker for CKD progression and its implications in the management of oxidative stress in CKD. Further research is warranted to elucidate the underlying mechanisms and explore the therapeutic potential of citrulline supplementation in CKD patients.
#1664 Assessing vascular access thrombectomy service adherence to GIRFT recommendations: single centre experience
Authors: Donne Rosemary , Eltahan Alshymaa , Pondor Zulfikar , Lewis David , Raman Maharajan , Gleave Paula , Poulikakos Dimitrios
Published: May 2024

Background and Aims

Studies showed that early thrombectomy of dialysis vascular access (VA) is associated with better outcomes [1], especially for native VA [2]. Timely treatment of VA thrombosis within 24-48 hours is recommended by GIRFT to minimize access loss and requirement for dialysis line insertion [3]. Our centre has approximately 430 HD patients but has no on-site vascular surgery or vascular access interventional radiology (IR) service. Wait time for elective VA surgery or fistuloplasty is >8 weeks and VA surveillance is based on routine clinical monitoring. VA prevalence is 62% AV fistula (AVF), 2% AV graft (AVG), 36% central venous catheter (CVC). Fistula thrombectomy is provided at another centre, with increasing waiting times over recent years due to shortage of interventional radiologists. This study evaluates adherence to GIRFT recommendations for patients at our centre requiring thrombectomy and will identify potential local strategies to reduce fistula thrombosis and CVC use.

Method

In a 24-months’ retrospective cohort analysis of maintenance HD patients with permanent VA, we obtained data on:

Results

44 patients with permanent VA developed VA thrombosis. The median waiting time for thrombectomy was 8 days (Fig. 1). Post-intervention primary patency rate was 71% at 3-months and 60% at 6-months (Fig. 2). 61% of patients required hospital admission with a 12-day median length of stay, with total inpatient admission days of 403 days over 2 years (2022-2023), and total cost of £246,065 (Figs. 3 and 4). The median CFD-extended was 356 days, i.e. 9 days/patient/year with VA-related complications (Fig. 5).

Conclusion

This study shows that our centre's VA thrombectomy service falls far outside the GIRFT recommendation of intervention within 24-48 hours. The high associated rates of CVC use, inpatient bed days and avoidable costs place a heavy burden on patient outcomes and NHS resources. The ideal solution of an on-site thrombectomy service is difficult to achieve due to lack of vascular IR support. In response to this study, we now aim to reduce thrombosis rates by training additional interventional nephrologists in elective fistuloplasty, implementing a robust VA surveillance to improve early detection of malfunctioning VA suitable for elective intervention and improving staff education on fistula care.
#2075 Impact of chronic obstructive pulmonary disease on the outcomes of hemodialysis patients
Authors: Hagai Keren Cohen , Benchetrit Sydney , Wand Ori , Amer Abu Husseine
Published: May 2024

Background and Aims

Chronic obstructive pulmonary disease, COPD, is a common cause of morbidity and mortality. Comorbidities are frequent among COPD patients, some of which are explained by shared risk factors of smoking and increased age. Chronic kidney disease, leading to end-stage renal disease requiring hemodialysis (HD) is not uncommon in patients with COPD, and vice-versa. The prevalence and the impact of coexistence of COPD among HD patients was not extensively described.

We aimed to measure the prevalence of COPD among a cohort of HD patients, and study how it relates to significant outcomes of mortality, morbidity, including unplanned hospital admissions, and kidney transplantation (KT).

Method

A retrospective study of subjects who initiated HD during 2015-2018. Participants were categorized into one of two groups, with or without COPD. Clinical, laboratory and pulmonary function tests data were extracted from medical records, as were outcomes of mortality, morbidity, and KT (until December 31st, 2021, or until death).

Results

Forty-three of 234 were diagnosed with COPD (18.4%). Their average FEV1%pred was 60%. Thirty-eight subjects in the COPD group (88.4%) were hospitalized for severe COPD exacerbations during a mean follow-up of 36.1 months, averaging 3.6 severe exacerbations per patient. Despite this, maintenance inhaler therapy was underutilized.

All-cause mortality rates were higher for HD patients with COPD (72.1% vs. 47.1%, p=0.003), as were rates of acute coronary syndrome (39.5% vs. 23.6%, p=0.026).

Conclusion

COPD is common among HD patients and is associated with significant morbidity and increased mortality.
#829 Renoprotective effects of laxative linaclotide: inhibition of acute kidney injury and fibrosis in a rat model of renal ischemia-reperfusion
Authors: Hitaka Yukihiro , Yamaguchi Misuhiro , Nakamura Kimihiko , Toshiya Hiroyoshi , Isoyama Naohito , Nagao Kazuhiro , Tsuji Shunya , Asagiri Asagirimasataka , Shiraishi Koji
Published: May 2024

Background and Aims

Acute kidney injury caused by renal ischemia/reperfusion (I/R) is a major clinical problem in many aspects of urology fields such as kidney transplantation and partial nephrectomy, but there is no effective treatment. Linaclotide, a guanylate cyclase C agonist clinically approved as a laxative, has recently been shown to be renoprotective in a chronic kidney disease (CKD) model. Therefore, the present study investigated the possibility that the renoprotective effects of linaclotide in renal I/R may extend beyond its gastrointestinal effects.

Method

The left renal pelvis of adult male Wistar rats was clamped for 45 minutes to induce renal I/R injury. Kidney tissue, colon, and blood were collected 24 hours and 14 days later. Linaclotide was administered for 14 days preoperatively and until postoperative tissue collection. Tissue sections were stained with standard histologic techniques such as HE, Sirius Red, F4/80, etc. As genes associated with I/R, TGF-β and related fibrosis markers α-SMA, MMP2, TIMP1 and inflammatory cytokines TNF, IL-1β and IL-6 were analyzed by quantitative PCR analysis.

Results

Serum creatinine levels decreased significantly after linaclotide administration, indicating improved renal function. Histologic examination showed less tubular damage and less collagen deposition on Sirius Red staining. Further analysis showed decreased expression of TGF-β and related fibrosis markers α-SMA, MMP2 and TIMP1, suggesting downregulation of the fibrotic TGF-β pathway by linaclotide. Furthermore, 1 day after I/R injury, linaclotide significantly reduced macrophage infiltration and suppressed key proinflammatory cytokines such as TNF, IL-1β, and IL-6.

Conclusion

These results suggest that linaclotide, with its established safety profile, could extend its benefits beyond gastrointestinal issues and potentially serve as a therapeutic intervention in many aspects of kidney surgeries. In addition, it could provide immediate and practical insights into the selection of laxatives for the management of patients with AKI or CKD, regardless of cause, and for those receiving dialysis or transplant therapy.
#804 The nonlinear association between body mass index and chronic kidney disease: a prospective cohort study and Mendelian randomization analysis
Authors: Zeng Xiaoxi , Yu Zhenzhen , Chen Jing
Published: May 2024

Background and Aims

Previous studies mainly focused on linear association between body mass index (BMI) and the risk of chronic kidney disease (CKD). In the current research, we conducted a prospective cohort observational study and Mendelian Randomization analysis to explore whether non-linear relationship exists between BMI and CKD.

Method

In the prospective cohort study, 495,465 participants from the UK biobank were included. The Cox proportional hazards model with fractional polynomial transformation was used to estimate the hazard ratio of BMI for incident CKD. In addition, nonlinear Mendelian Randomization analysis was performed using the fractional polynomial method to verify the causality of the association.

Results

In the observational analysis, a J-shaped association was observed between BMI and the risk of CKD. The risk of CKD was lowest when the BMI was around 18-20 kg/m2, and the hazard of developing CKD increased in participants with lower or higher BMI (Fig. 1). When assessing the causal relationship, in Mendelian Randomization analysis, despite that a nonlinear relationship still held true (P-value for non-linearity = 0.008), the odds ratio for CKD monotonically rised with increasing BMI (Fig. 2).

Conclusion

The J-shape association between BMI and CKD revealed by the observational cohort study was not supported by the Mendelian Randomization, which indicated a monotonically causal relationship that the risk of CKD rised with increasing BMI.
#305 Global health inequalities of CKD: a systematic review and meta-analysis examining prevalence and disparities in age, sex and socio-economic status
Authors: Duff Rachael , Awofala Omodolapo , Arshad Muhammad Tahir , Lambourg Emilie , Gallacher Peter , Dhaun Neeraj , Bell Samira
Published: May 2024

Background and Aims

Chronic kidney disease (CKD) is a significant contributor to global morbidity and mortality. Age, sex and socio-economic status are considered to be influential in the development, progression and outcomes from CKD. This study investigated disparities in age, sex and socio-economic status in CKD and updated global prevalence estimates through systematic review and meta-analysis.

Method

Five databases (MEDLINE/PubMed, Embase, Cochrane CENTRAL Library, CINAHL, Web of Science) were searched from 2014 to 2022, with 14,871 articles screened, 119 papers included and data analysed on 29,159,948 participants. Studies were included if they described CKD prevalence in participants over the age of 18 and were carried out in the general population. CKD was defined on the basis of albuminuria/proteinuria and/or an estimated glomerular filtration rate of <60 ml/min/m2. Random effects meta-analyses using generalised linear mixed models were conducted to determine overall prevalence, prevalence of stages 3–5 and prevalence in males and females. Influences of age, sex and socio-economic status were assessed in subgroup analyses, and risk of bias assessment and meta-regressions were conducted to explore heterogeneity.

Results

Overall prevalence of CKD was 13.0% (11.3–14.8%) and 6.6% (5.6–7.8%) for stages 3–5. Prevalence was higher in studies where all participants were over the age of 60 (19.3% for stages 1–5. 15.0% for stages 3–5) and meta-regression demonstrated association of age, body mass index, diabetes and hypertension with prevalence of CKD stages 3–5. The prevalence of CKD stages 1–5 was similar in males and females (13.1% versus 13.2%) but prevalence of stages 3–5 was higher in females (6.4% versus 7.5%). Overall prevalence was 11.4%, 15.0% and 10.8% in low, middle and high-income countries respectively; for stages 3–5 prevalence was 4.0%, 6.7% and 6.8%, respectively. Risk of bias of included studies was generally moderate or high, with 8% at low risk of bias, 44% at moderate risk of bias and 48% at high risk of bias.

Conclusion

With nearly 30 million participants, this study is the largest systematic review on CKD prevalence to date, with prevalence demonstrated to be persistently high globally. It has highlighted that important disparities related to age, sex and socio-economic status may exist, and addressing these concerns should be a priority for policymakers. Future research should focus on targeted screening and treatment approaches, improving access to care and more effective data monitoring, particularly in low and middle income countries.
#2717 Fermentable and viscous dietary fiber types improve cortical bone in a rat model of chronic kidney disease-mineral and bone disorder
Authors: Biruete Annabel , Metzger Corinne , Blacklock Karis , Srinivasan Shruthi , O'neill Kalisha , Siles Samantha , Gallant Kathleen Hill , Allen Matthew , Chen Neal X , Moe Sharon
Published: May 2024

Background and Aims

Renal osteodystrophy is highly prevalent among people with chronic kidney disease (CKD). We recently showed that inulin, a prebiotic fermentable dietary fiber, improved cortical bone parameters in rats with moderate-to-severe CKD. Our objective was to evaluate if this effect was unique to the prebiotic fibers or if other fiber properties, such as viscosity, could be beneficial to bone in a rat model of CKD-mineral and bone disorder (CKD-MBD).

Method

22-week-old Cy/+ male rats (50% kidney function compared to normal; CKD hereafter) were randomly assigned to receive one of four fiber treatments (10% w/w each) based on fermentability and viscosity: 1) Cellulose (−fermentability, −viscosity), 2) Inulin (+fermentability, −viscosity), 3) Psyllium husk (−fermentability, +viscosity), or 4) Pectin (+ fermentability, +viscosity). These diets were formulated with a semi-purified, casein-based background diet with 0.7% calcium and 0.7% phosphorus. Treatments lasted 10 weeks, and rats were euthanized at 32 weeks of age (kidney failure; ∼15% of normal). Micro-computed tomography (μCT) at 12-μm resolution was performed on the proximal tibia. Serum creatinine, plasma phosphorus, and plasma calcium were analyzed using colorimetric assays. One-way ANOVA was used to test the effect of dietary fiber types on outcome measures.

Results

At 32 weeks of age, serum creatinine was lower in the inulin, psyllium, and pectin-treated CKD rats (<0.04). Plasma calcium concentrations were similar between treatments, but phosphorus was lower in the psyllium and pectin-treated CKD rats (p < 0.02). Bone cortical area was higher in the inulin and psyllium-treated CKD rats compared to cellulose-treated rats (p < 0.007). Cortical thickness was higher in the inulin, psyllium, and pectin-treated CKD rats compared to cellulose-treated rats (p < 0.02). There was less cortical porosity in the inulin, psyllium, and pectin-treated rats (p < 0.02). Fermentable or viscous fibers did not impact trabecular bone volume, thickness, spacing, and number (p < 0.05). Plasma phosphorus was negatively associated with cortical area (r = −0.56; p < 0.0001) and cortical thickness (r = −0.75; p < 0.0001), and positively associated with cortical porosity (r = 0.74; p < 0.0001).

Conclusion

Fermentable and viscous fibers improved cortical bone but had no effect on trabecular bone. This effect may be, at least in part, due to the fiber's ability to lower plasma phosphorus and likely parathyroid hormone.
#1506 Uremic toxicity: gaining novel insights through AI-driven literature review
Authors: Zhang Hanjie , Kotanko Peter
Published: May 2024

Background and Aims

The rapidly growing scientific literature poses a significant challenge for researchers seeking to distill key insights. We utilized Retrieval-Augmented Generation (RAG), a novel AI-driven approach, to efficiently process and extract meaningful information from published literature on uremic toxins. RAG is a general AI framework for improving the quality of responses generated by Large Language Models (LLMs) by supplementing the LLM's internal representation of information with curated expert knowledge.

Method

First, we collected on PubMed all abstracts related to the topic of “uremic toxins” through Metapub, a Python library designed to facilitate fetching metadata from PubMed. Second, we set up a RAG system that comprises 2 steps. In a retrieval step, the questions on topic (“uremic toxins”) and the documents (=all collected abstracts and manuscripts) are encoded into vectors (i.e., high-dimensional numerical representations). Similarity measures are used to find the best matches between documents and the questions on topic. Second, in the augmented generation step, the LLM (e.g., ChatGPT) uses these best matches of documents to generate a coherent and informed response.

Results

We collected 3497 abstracts from the PubMed and 191 expert-curated publications in PDF format related to the topic “uremic toxin”. These 191 publications were broken down to 5756 documents, each with a manageable size of text. The final vector database comprised 9253 vectors. Using RAG, we requested responses from the LLM on multiple questions related to “uremic toxins”. Some examples are shown in Table 1. The first and second responses given by the LLM are reasonable. However, the third answer shows the phenomenon of ‘hallucination’—where models generate plausible and convincingly sounding yet factually incorrect information.

Conclusion

The use of RAG improves the capability of LLMs to answer questions by leveraging the information contained within curated abstracts and publications. Despite the improvements with RAG, the phenomenon of ‘hallucination’ persists. A concerning feature of hallucinations is their eloquent and convincing language. For the time being, LLM output—even when improved with RAG—requires scrutiny and human verification.
High-value breast cancer care within resource limitations
Authors: Verhoeven Didier , Siesling Sabine , Allemani Claudia , Roy Pankaj Gupta , Travado Luzia , Bhoo-Pathy Nirmala , Rhayns Clifford , Junkermann Hans , Nakamura Seigo , Lasebikan Nwamaka , Tucker Forrest Lee
Published: May 2024

Breast cancer care is a costly global health issue where effective management depends on early detection and treatment. A breast cancer diagnosis can result in financial catastrophe especially in low- and middle-income countries (LMIC). Large inequities in breast cancer care are observed and represent a global challenge to caregivers and patients. Strategies to improve early diagnosis include awareness and clinical breast examination in LMIC, and screening in high-income countries (HIC). The use of clinical guidelines for the management of breast cancer is needed. Adapted guidelines from HIC can address disparities in populations with limited resources. Locally developed strategies still provide effective guidance in improving survival. Integrated practice units (IPU) with timely multidisciplinary breast care conferences and patient navigators are required to achieve high-value, personalized breast cancer management in HIC as well as LMIC. Breast cancer patient care should include a quality of life evaluation using ideally patient-reported outcomes (PROM) and experience measurements (PREM). Evaluation of breast cancer outcomes must include the financial cost of delivered care. The resulting value perspective should guide resource allocation and program priorities. The value of care must be improved by translating the findings of social and economic research into practice and resolving systemic inequity in clinical breast cancer research. Cancer survivorship programs must be put in place everywhere. The treatment of patients with metastatic breast cancer must require more attention in the future, especially in LMIC.
Cybersecurity, Ethics, and Collective Responsibility
Authors: Miller Seumas , Bossomaier Terry
Published: May 2024

The advent of the internet, the exponential growth in computing power and the rapid developments in artificial intelligence have given rise to numerous ethical questions in relation to cybersecurity across various domains, not least by virtue of the dual-use character of cybertechnology—it can be used to provide great benefits to humankind, but also to do great harm. The domains in question intersect and include business (e.g., data security, data ownership and privacy), public communication (e.g., disinformation and computational propaganda), health (e.g., privacy, ransomware attacks), law enforcement (e.g., data security, predictive policing), and interstate conflict (e.g., cyberwar, autonomous weapons). This work undertakes analyses of the key ethical concepts in play, such as privacy, freedom of communication, security, and the right to self-defence. This work also develops sets of ethical guidelines to give direction to the regulation of cyberspace in these various domains. It does so from a liberal democratic perspective that seeks to protect individual rights while ensuring the collective good of cybersecurity. A central informing idea is that of institutionally embedded collective moral responsibilities that function as “webs of prevention” against cyberattacks. Cybersecurity is, in the end, a collective moral responsibility of both individual citizens and organizations, but a collective responsibility the discharging of which requires new regulation and the redesign of institutional roles, as well as technical countermeasures to cyberattacks, such as passwords, encryption, firewalls, patching, and the like. It also involves at times, we suggest, offensive as well as defensive measures.
Romance and Identity
Authors: Henley Georgia
Published: May 2024

Chapter 4 focuses on three romances set in marcher contexts. The romance of Fouke le Fitz Waryn, set initially in Shropshire, depicts the disinheritance of Fouke III de Waryn (d. 1258) and his subsequent adventures during exile on the continent and in Wales, where he is assisted by his childhood companion Llywelyn ab Iorwerth. The History of William Marshal portrays the exceptional life of William Marshal (c.1146–1219) in chivalric terms, while The Awntyrs off Arthure at the Terne Wathelyn provides a counter-example of Arthurian border literature from the Anglo-Scottish borderlands. Whereas previous analyses have considered these romances in the context of other ‘ancestral romances’ or family romances from Anglo-Norman England, this chapter shows that these texts are primarily occupied by marcher concerns, such as land rights, independence, and the need for jurisdictional limits on the English Crown. Placing these texts in a marcher context, rather than a strictly English context, allows a more focused articulation of their interests to emerge. In particular, marcher literature is interested in the Welsh past, the strain of British history and prophecy indebted to Geoffrey of Monmouth, the idea of women as key players in lines of succession of lordships (especially in cases where there is no living male heir), and defensive ownership of and claim to land in Wales and the Marches.
Elegies for Welsh Princes
Authors: Henley Georgia
Published: May 2024

This chapter turns to elegy as a mode of historical writing deeply rooted in memory and affective experience. It focuses on English chroniclers’ inclusion of elegies to Welsh princes of the twelfth and thirteenth centuries, Rhys ap Gruffudd (d. 1197) and Llywelyn ap Gruffudd (d. 1282). Written in Wales, these elegies, included in Latin chronicles from England and the Marches, such as Higden’s Polychronicon, Trevisa’s Chronicle, the Annals of Chester, and Camden’s Britannia, record English perspectives on Welsh history. In memorializing fallen leaders, chroniclers used elevated rhetoric to heighten the immediacy of the past. Heightened rhetoric immersed the reader in the past and created a sense of continuity across historical time, particularly through references to Greek and Latin heroes. The elegy also provided a crucial sense of distance by portraying threatening Welsh leaders as unequivocally past. The reader was meant to identify with the Welsh and experience the deep sense of loss and fragmentation that the deaths of their princes represented. But the elegiac mode also provided a crucial sense of remove, memorializing Welsh princes as if they were classical heroes: evocative, but no longer a threat. These chronicles’ recollections of Welsh loss attest to the ability of elegiac verse to transgress and to break down boundaries of culture through affective experience while still protecting cultural dominance. This study of Welsh elegies in English contexts demonstrates a key outcome of marcher interest in Wales and the Welsh past: the transmission of Welsh texts beyond the borderlands of Wales and into England.
Introduction
Authors: Stauffer George B.
Published: May 2024

The introduction explores the rich musical life of Central Germany in Bach’s time. Music pervaded court, municipal, and church activities, requiring the composition, preparation, and performance of vast amounts of new music on a weekly—if not daily—basis. In his youth, Bach was surrounded by music and music-making. Also of critical importance in his upbringing was the primary role of the pipe organ in Central German culture. As the largest and most complex machine in Western civilization at the time, the pipe organ was the subject of veneration, awe, and civic pride. In Central and North Germany it was a critical architectural component of the Lutheran church, together with the pulpit, baptismal font, and altar. The final section of the introduction focuses on the ways Bach’s organ works were preserved after his death, in autograph manuscripts, original prints, and copies made by his sons, students, and followers.
The Young Bach
Authors: Stauffer George B.
Published: May 2024

Chapter 1 examines Bach’s upbringing and early training in Eisenach, Ohrdruf, Lüneburg, and Weimar. Born into a family of musicians in Eisenach, Bach was orphaned at the age of 10 and taken in by his older brother, Johann Christoph, an organist in Ohrdruf. After receiving his initial training in keyboard playing from Johann Christoph, who had studied with Pachelbel and owned a sizable collection of Central and North German keyboard works, Bach traveled to Lüneburg to complete his academic studies and sing in the choir of the St. Michael’s Latin School. During this time Georg Böhm took Bach under his wing. Bach also ventured several times to Hamburg, to see the large organs there and hear Johann Adam Reincken, dean of the North German organists. He was clearly dazzled by both. Bach’s training ended with a short stint as music factotum at the Weimar Court.
Small Chorale Settings
Authors: Stauffer George B.
Published: May 2024

Chapter 11 is devoted to the small chorale settings Bach composed in Weimar—miscellaneous manual works, chorale fughettas, and pieces earmarked for the accompaniment of congregational hymns: figured-bass and interlude settings. Here, too, Bach demonstrated astonishing imagination, taking the manual chorale to unparalleled heights. Of special interest is the series of chorale fughettas that Bach appears to have composed as a set, systematically exploring the compositional possibilities of this popular Central German genre. The use of interlude settings for congregational singing is also discussed at some length, with a special focus on the settings Bach seems to have set down in abbreviated form before fully fleshing them out for practical use. Attention is also given to the abuse of interlude settings by contemporary organists and Bach’s late comments on the practice.
Organ Teacher, Consultant, and Recitalist
Authors: Stauffer George B.
Published: May 2024

In chapter 15, Bach’s interest in didactic works in Cöthen serves as the springboard for a discussion of his role as organ pedagogue, organ consultant, and organ recitalist. The handful of organ pieces Bach wrote in Cöthen point to instructional interests. Small manual chorale preludes illustrate the art of ornamentation, and the incomplete Fantasy in C Major, BWV 573, demonstrates the process of composing a short organ prelude. The Orgel-Büchlein, written in Weimar, was now repurposed for teaching. Moreover, Bach was frequently asked to inspect and inaugurate new instruments and provide advice on their design. Extant reports show that he was a thorough but fair examiner. Bach’s reputation as a virtuoso performer also grew during the Cöthen years, and as a consequence he was increasingly in demand as an organ recitalist. His concert in Hamburg in 1720, praised by Johann Adam Reincken, marked the first of several triumphant organ recitals in large German cities.
Bach’s Art of Registration
Authors: Stauffer George B.
Published: May 2024

Chapter 16 is devoted to Bach’s treatment of organ registration. It begins with a comparison of French and English practices before looking at the German tradition in Bach’s time. Organ registrations in Germany were generally divided into two categories: the full organ (organum plenum) and all the remaining diverse possibilities. The full organ, a combination of carefully selected stops, was used for free organ works and certain chorale preludes written in an instrumental or vocal style. Smaller, more colorful registrations, often calling for the use of two manuals and pedal, were used for chorale settings, duos, and trios. Hymn accompaniment required registrations that reflected both the nature of the hymn in question and the makeup of the congregation. According to contemporary accounts, Bach registered the organ in a unique way. The indications for specific stops found in surviving sources, though few in number, provide a glimpse of his approach.
Bach in Leipzig
Authors: Stauffer George B.
Published: May 2024

In 1723 Bach left Cöthen to assume the post of St. Thomas cantor and town music director in Leipzig. Bach approached his new position with great energy, initially composing almost 300 church cantatas before taking up the directorship of the “Telemann” Collegium Musicum and then, late in life, turning to private projects. Chapter 17 examines the effect of these undertakings on Bach’s organ music, which include the influence of his cantatas, the fusion of national and historical styles, and the increased role of revision and recycling. Also coming into play was the shift in Central German organ building toward instruments that could produce chamber-music sounds. While the early biographer Philipp Spitta called the Weimar years the “Golden Period” of Bach’s organ writing, the Leipzig years were perhaps even more remarkable, since many of the organ works Bach composed during his final decades forged new ground and pointed to styles of the future.
Cantata and Passion Movements with Obbligato Organ and Miscellaneous Trios
Authors: Stauffer George B.
Published: May 2024

Bach’s return to organ composition in Leipzig after a hiatus of almost 10 years took the form of cantata movements featuring obbligato organ. Seventeen such movements suddenly appeared in a series of six cantatas written for the third cantata cycle in 1726, and Bach went on to compose an additional 12 obbligato movements in later years. The instrument involved was not the small portative organ used in most recordings and performances today but the large type of organ found in the St. Thomas and St. Nicholas churches in Leipzig. The cantata music paved the way for the innovative Six Sonatas, which appeared just a few years later. Also pointing to the Sonatas is a series of trio transcriptions and compositions that emanated from Bach’s workshop between 1725 and 1730 or so. Chapter 18 examines these developments, as a prelude to the discussion of the Six Sonatas in chapter 19.
Nineteen Large Chorales of Various Sorts
Authors: Stauffer George B.
Published: May 2024

Around 1739 Bach began to assemble a portfolio of chorale settings written earlier, mostly during the Weimar period. He initially entered 13 settings into the portfolio before laying it aside to focus on other things. He returned to the collection some years later, first adding two more chorale settings and then a revised version of the Canonic Variations on “Vom Himmel hoch,” BWV 769a. At a still later point, his son-in-law Johann Christoph Altnickol inserted two more settings, and an unidentified scribe entered the deathbed chorale, “Vor deinen Thron tret ich hermit,” BWV 668. These final entries appear to have taken place after Bach was blind and bedridden from eye operations performed in March 1750. The portfolio, the topic of chapter 25, shows Bach’s determination to preserve chorale preluding practices of the past as well as his desire to bring his music, through revision, to a still higher level of perfection.
The Case for Evidence-Based Parent Education Programs in Family Dispute Resolution
Authors: Sandler Irwin , O’Hara Karey , Wolchik Sharlene A. , Salem Peter
Published: May 2024

This chapter makes the case for evidence-based parent education in the family courts. First, the authors review the history and current status of parent education in the family court and provide a decision matrix that courts can use to prioritize parent education for families. Second, they review evidence that children from divorced families are at risk for multiple problems and describe factors that mitigate that risk. Third, they review research that demonstrates the effectiveness of parent education for a broad spectrum of populations. Finally, they present a comprehensive review of research that supports the efficacy of some parent education programs to strengthen parenting, reduce interparental conflict, and reduce children’s problems following divorce. They also note that many parent education programs currently offered through the courts lack evidence of effectiveness. They conclude that family courts can make a significant contribution to the well-being of children by offering evidence-based parent education programs.
Prime Directive
Authors: Cook Steven A.
Published: May 2024

Chapter 2 explores the evolution of the American commitment to secure the free flow of oil from the Middle East. That American mission progressed slowly in the decades following World War II but developed rapidly in the 1970s. The chapter focuses on a series of policies that Washington advanced starting with the Nixon Doctrine—also known as the Twin Pillars strategy—moving through the Carter Doctrine, and the Reagan Corollary, and on to Operation Desert Shield/Desert Storm and the Dual Containment of the 1990s. Despite setbacks like the 1973 Arab oil embargo and the Iranian Revolution in 1979 that caused shocks to the global oil supply, they were quickly overcome. Overall, Washington was successful in its efforts to ensure the free flow of energy, but at the cost of its ideals and principles, given that the United States partnered with a variety of the Middle East’s authoritarian leaders to achieve this important goal.
The Aborted Revolution
Authors: Cook Steven A.
Published: May 2024

Chapter 5 highlights the abortive efforts of presidents Obama and Trump to correct the mistakes of the previous decades and contain the transformative ambitions of US foreign policy. It demonstrates that the Obama administration deviated from this goal when it put the United States back in the democracy-promotion business after the Arab uprisings and when it negotiated the JCPOA. Despite protestations from officials to the contrary, central to the nuclear agreement was the idea that it would transform US-Iran relations and thus the regional geostrategic order. For his part, President Trump took up the rhetoric of “ending forever wars,” but his approach to the Middle East was incoherent, including both escalation and de-escalation in the region.