Identification of QTLs for symbiotic nitrogen fixation and related traits in a soybean recombinant inbred line population.

KEY MESSAGE: The genetic architecture of symbiotic N fixation and related traits was investigated in the field. QTLs were identified for percent N derived from the atmosphere, shoot [N] and C to N ratio. Soybean [Glycine max (L.) Merr.] is cultivated worldwide and is the most abundant source of plant-based protein. Symbiotic N2 fixation (SNF) in legumes such as soybean is of great importance; however, yields may still be limited by N in both high yielding and stressful environments. To better understand the genetic architecture of SNF and facilitate the development of high yielding cultivars and sustainable soybean production in stressful environments, a recombinant inbred line population consisting of 190 lines, developed from a cross between PI 442012A and PI 404199, was evaluated for N derived from the atmosphere (Ndfa), N concentration ([N]), and C to N ratio (C/N) in three environments. Significant genotype, environment and genotype × environment effects were observed for all three traits. A linkage map was constructed containing 3309 single nucleotide polymorphism (SNP) markers. QTL analysis was performed for additive effects of QTLs, QTL × environment interactions, and QTL × QTL interactions. Ten unique additive QTLs were identified across all traits and environments. Of these, two QTLs were detected for Ndfa and eight for C/N. Of the eight QTLs for C/N, four were also detected for [N]. Using QTL × environment analysis, six QTLs were detected, of which five were also identified in the additive QTL analysis. The QTL × QTL analysis identified four unique epistatic interactions. The results of this study may be used for genomic selection and introgression of favorable alleles for increased SNF, [N], and C/N via marker-assisted selection.

Identification of novel glucocerebrosidase chaperones by unexpected skeletal rearrangement reaction.

Compound 5 was identified from a high-throughput screening campaign as a small molecule pharmacological chaperone of glucocerebrocidase (GCase), a lysosomal hydrolase encoded by the GBA1 gene, variants of which are associated with Gaucher disease and Parkinson's disease. Further investigations revealed that compound 5 was slowly transformed into a regio-isomeric compound (6) in PBS buffer, plausibly via a ring-opening at hemiaminal moiety accompanied by subsequent intramolecular CC bond formation. Utilising this unexpected skeletal rearrangement reaction, a series of compound 6 analogues was synthesized which yielded multiple potent GCase pharmacological chaperones with sub-micromolar EC50 values as exemplified by compound 38 (EC50 = 0.14 µM).

De Novo Synthesis of Dihydrobenzofurans and Indolines and Its Application to a Modular, Asymmetric Synthesis of Beraprost.

Dihydrobenzofurans and indolines are important constituents of pharmaceuticals. Herein, we describe a novel strategy for their construction in which the aromatic ring is created de novo through an inverse-electron demand Diels-Alder reaction and cheletropic extrusion sequence of a 2-halothiophene-1,1-dioxide with an enol ether/enamide, followed by aromatization. Unusually, the aromatization process proved to be highly challenging, but it was discovered that treatment of the halocyclohexadienes with a base effected an α-elimination-aromatization reaction. Mechanistic investigation of this step using deuterium-labeling studies indicated the intermediacy of a carbene which undergoes a 1,2-hydrogen shift and subsequent aromatization. The methodology was applied to a modular and stereoselective total synthesis of the antiplatelet drug beraprost in only 8 steps from a key enal-lactone. This lactone provided the core of beraprost to which both its sidechains could be appended through a 1,4-conjugate addition process (lower ω-sidechain), followed by de novo construction of beraprost's dihydrobenzofuran (upper α-sidechain) using our newly developed methodology. Additionally, we have demonstrated the breadth of our newly established protocol in the synthesis of functionalized indolines, which occurred with high levels of regiocontrol. According to density-functional theory (DFT) calculations, the high selectivity originates from attractive London dispersion interactions in the TS of the Diels-Alder reaction.

Evaluation of exotic soybean accessions and their use in developing improved soybean lines with resistance to Phomopsis seed decay.

Poor seed quality of soybean is often associated with Phomopsis seed decay (PSD), which is one of the most economically important seed diseases. Diaporthe longicolla (syn. Phomopsis longicolla) is the primary cause of PSD. Control of PSD is best accomplished by planting PSD-resistant cultivars. Sixteen exotic soybean accessions from the USDA soybean germplasm collection were screened for reaction to PSD at Stoneville, Mississippi. They consisted of maturity groups (MG) II, III and IV. Seeds from inoculated and non-inoculated plots harvested either promptly at maturity, or after a two-week delay in harvest, were assessed for infection by D. longicolla. Seed infection ranged from 0 to 36.7%. Overall, PI 417050 (MG II), PI 417017 (MG III), and PI 594692 (MG IV) had significantly (P ≤ 0.05) lower percentages of seed infected by D. longicolla and higher seed germinations than other genotypes in the same maturity groups. PI 587982A also performed well. As a result of these findings, these resistant accessions were used over multiple cycles of breeding to develop improved breeding lines with resistance to PSD and low seed damage. Breeding line 11043-225-72, with combined resistance from both PIs 417050 and 587982A, had low scores for PSD (6.7%) and seed damage (3.4%), while DS65-1, deriving resistance from PI 587982A, had the lowest seed damage score (1.1%) and the highest seed germination (85.6%) among all lines tested in 2017. DS65-1 and 11043-225-72, along with five other improved breeding lines, were provided to public soybean breeders for developing improved cultivars and germplasm lines. DS31-243 (PI 700941), derived from PI 587982A, was publicly released by the USDA in 2022. This research will lead to future releases of improved germplasm lines and cultivars with PSD resistance and high seed quality. It will also aid in disease management and be a benefit to soybean producers and the industry at large.

Phenotypic Evaluation of Soybean Genotypes for Their Reaction to a Mississippi Isolate of Phakopsora pachyrhizi Causing Soybean Rust.

Soybean rust (SBR) caused by Phakopsora pachyrhizi Syd. and P. Syd. is one of the most important foliar diseases of soybean. SBR has the potential to cause major economic damage to global and U.S. soybean production. Analysis of reactions of soybean genotypes to P. pachyrhizi is an important step towards breeding for resistance to SBR. Fifty-four diverse soybean genotypes with both known and unknown Rpp resistance genes were tested for their reactions to a Mississippi P. pachyrhizi isolate. PI 567102B (Rpp6) had a near-immune reaction with the lowest disease severity score and no sporulation. Among seventeen genotypes with resistant or incomplete resistant reddish-brown (RB) reactions, eight are improved breeding lines that are available to researchers through material transfer agreements (MTAs). Thirty-six genotypes had the susceptible TAN reaction. Four soybean lines (RN06-32-1(7-b, GC 00138-29, G01-PR16, and GC 84051-9-1) had RB reactions and significantly lower SBR severity and sporulation than three of the six resistant checks, PI 230970 (Rpp2), PI 462312 (Rpp3), and PI 459025B (Rpp4). G01-PR16 is a publicly released germplasm. This research provides new information about reactions of different soybean genotypes to a midsouthern USA isolate of P. pachyrhizi and thereby aids in breeding for resistance to SBR.

Is it safe for patients with metal implants to have iontophoresis treatment?

BACKGROUND: Iontophoresis passes electrical charge through skin to deliver drugs or reduce excessive sweating. Treatments can be performed by patients at home following initial instruction. A limitation of the technique is that patients are not permitted to have metal implants. These are hypothesized to increase the risk of electric shock, cause localized heating and/or corrosion. OBJECTIVES: To investigate whether metallic materials (titanium, stainless steel and copper) placed in the iontophoresis circuit would lead to an unfavourable outcome regarding corrosion or local heating of the metallic object. METHODS: This was carried out using mass loss and temperature change experiments, together with atomic force microscopy for stainless steel, to assess any surface roughness changes. The investigations were carried out under accelerated conditions (70 V compared with standard use 20-30 V). RESULTS: No changes in mass or clinically significant changes in temperature of any of the metallic objects (or surface roughness for stainless steel) were observed. CONCLUSIONS: This study suggests that patients with these metallic implants can safely undergo iontophoresis treatment. Further work is needed to review the impact on metallic implants with repeated exposure to the iontophoresis system to represent real-world evidence.

Soybean Seed Sugars: A Role in the Mechanism of Resistance to Charcoal Rot and Potential Use as Biomarkers in Selection.

Charcoal rot, caused by Macrophomina phaseolina, is a major soybean disease resulting in significant yield loss and poor seed quality. Currently, no resistant soybean cultivar is available in the market and resistance mechanisms to charcoal rot are unknown, although the disease is believed to infect plants from infected soil through the roots by unknown toxin-mediated mechanisms. The objective of this research was to investigate the association between seed sugars (sucrose, raffinose, stachyose, glucose, and fructose) and their role as biomarkers in the soybean defense mechanism in the moderately resistant (MR) and susceptible (S) genotypes to charcoal rot. Seven MR and six S genotypes were grown under irrigated (IR) and non-irrigated (NIR) conditions. A two-year field experiment was conducted in 2012 and 2013 at Jackson, TN, USA. The main findings in this research were that MR genotypes generally had the ability to maintain higher seed levels of sucrose, glucose, and fructose than did S genotypes. Conversely, susceptible genotypes showed a higher level of stachyose and lower levels of sucrose, glucose, and fructose. This was observed in 6 out of 7 MR genotypes and in 4 out of 6 S genotypes in 2012; and in 5 out of 7 MR genotypes and in 5 out of 6 S genotypes in 2013. The response of S genotypes with higher levels of stachyose and lower sucrose, glucose, and fructose, compared with those of MR genotypes, may indicate the possible role of these sugars in a defense mechanism against charcoal rot. It also indicates that nutrient pathways in MR genotypes allowed for a higher influx of nutritious sugars (sucrose, glucose, and fructose) than did S genotypes, suggesting these sugars as potential biomarkers for selecting MR soybean plants after harvest. This research provides new knowledge on seed sugars and helps in understanding the impact of charcoal rot on seed sugars in moderately resistant and susceptible genotypes.

Identification of genomic regions associated with the plasticity of carbon 13 ratio in soybean.

Improving water use efficiency (WUE) for soybean [Glycine max (L.) Merr.] through selection for high carbon isotope (C13) ratio may increase drought tolerance, but increased WUE may limit growth in productive environments. An ideal genotype would be plastic for C13 ratio; that is, be able to alter C13 ratio in response to the environment. Our objective was to identify genomic regions associated with C13 ratio plasticity, C13 ratio stability, and overall C13 ratio in two panels of diverse Maturity Group IV soybean accessions. A second objective was to identify accessions that differed in their C13 ratio plasticity. Panel 1 (205 accessions) was evaluated in seven irrigated and four drought environments, and Panel 2 (373 accessions) was evaluated in four environments. Plasticity was quantified as the slope from regressing C13 ratio of individual genotypes against an environmental index calculated based on the mean within and across environments. The regression intercept was considered a measure of C13 ratio over all environments, and the root mean square error was considered a measure of stability. Combined over both panels, genome-wide association mapping (GWAM) identified 19 single nucleotide polymorphisms (SNPs) for plasticity, 39 SNPs for C13 ratio, and 16 SNPs for stability. Among these SNPs, 71 candidate genes had annotations associated with transpiration or water conservation and transport, root development, root hair elongation, and stomatal complex morphogenesis. The genomic regions associated with plasticity and stability identified in the current study will be a useful resource for implementing genomic selection for improving drought tolerance in soybean.

Biomimetic generation of the strongest known biomaterial found in limpet tooth.

The biomaterial with the highest known tensile strength is a unique composite of chitin and goethite (α-FeO(OH)) present in teeth from the Common Limpet (Patella vulgata). A biomimetic based on limpet tooth, with corresponding high-performance mechanical properties is highly desirable. Here we report on the replication of limpet tooth developmental processes ex vivo, where isolated limpet tissue and cells in culture generate new biomimetic structures. Transcriptomic analysis of each developmental stage of the radula, the organ from which limpet teeth originate, identifies sequential changes in expression of genes related to chitin and iron processing. We quantify iron and chitin metabolic processes in the radula and grow isolated radula cells in vitro. Bioinspired material can be developed with electrospun chitin mineralised by conditioned media from cultured radula cells. Our results inform molecular processes behind the generation of limpet tooth and establish a platform for development of a novel biomimetic with comparable properties.

Epidemiology and outcomes of tibial plateau fractures in adults aged 60 and over treated in the United Kingdom.

BACKGROUND: Tibial plateau fractures are common in older adults, often resulting from low-energy falls. Although lower limb fragility fracture care has evolved, the management of tibial plateau fractures in older patients remains poorly researched. This study aimed to define the epidemiology, treatment and outcomes of tibial plateau fractures in patients aged over 60 years. METHODOLOGY: Patients aged 60 years or older with a tibial plateau fracture who presented to a single trauma center between January 2008 and December 2018 were identified. Incomplete records were excluded. Epidemiological data, fracture classification, injury management, radiological outcomes, complications, and mortality were assessed via retrospective case note and radiograph review. Local ethics approval was obtained. RESULTS: Two-hundred and twenty patients with a mean age of 74 years (range 60-100) were included. 73% were female and 71% of injuries were sustained following low-energy falls. Median follow up was three months. 50% of fractures involved the lateral plateau. 60% of injuries were treated non-operatively. 76% of patients had their weight-bearing restricted for the first six weeks, with little difference between operatively and non-operatively managed patients. 8% of all patients required subsequent knee replacement. All-cause mortality at 30-days and one-year were 2% and 5% respectively. CONCLUSION: The majority of tibial plateau fractures in the over 60s are sustained from low-energy trauma. Management is relatively conservative when compared with younger cohorts. The data reported brings up questions of whether surgical treatment is beneficial to this patient group, or whether restricted weight bearing is either possible or beneficial. Prospective, multi-center comparative trials are needed to determine whether increased operative intervention or different rehabilitation strategies purveys any patient benefit.

The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver.

Fibrosis contributes to ~45% of deaths in western countries. In chronic liver disease, fibrosis is a major factor determining outcomes, but efficient antifibrotic therapies are lacking. Although platelet-derived growth factor and transforming growth factor-ß constitute key fibrogenic mediators, they do not account for the well-established link between cell death and fibrosis in the liver. Here, we hypothesized that damage-associated molecular patterns (DAMPs) may link epithelial cell death to fibrogenesis in the injured liver. DAMP receptor screening identified purinergic receptor P2Y14 among several candidates as highly enriched in hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Conversely, P2Y14 ligands uridine 5'-diphosphate (UDP)-glucose and UDP-galactose were enriched in hepatocytes and were released upon different modes of cell death. Accordingly, ligand-receptor interaction analysis that combined proteomic and single-cell RNA sequencing data revealed P2Y14 ligands and P2Y14 receptor as a link between dying cells and HSCs, respectively. Treatment with P2Y14 ligands or coculture with dying hepatocytes promoted HSC activation in a P2Y14-dependent manner. P2Y14 ligands activated extracellular signal-regulated kinase (ERK) and Yes-associated protein (YAP) signaling in HSCs, resulting in ERK-dependent HSC activation. Global and HSC-selective P2Y14 deficiency attenuated liver fibrosis in multiple mouse models of liver injury. Functional expression of P2Y14 was confirmed in healthy and diseased human liver and human HSCs. In conclusion, P2Y14 ligands and their receptor constitute a profibrogenic DAMP pathway that directly links cell death to fibrogenesis.

St Georg Sled medial unicompartmental arthroplasty: survivorship analysis and function at 20 years follow up.

PURPOSE: The peri-operative and short-term benefits of unicompartmental knee arthroplasty (UKA) are well supported in the literature. However, there remains concern regarding the higher revision rate when compared with total knee replacement. This manuscript reports the functional outcome and survivorship of a large series of fixed bearing, medial unicompartmental replacements (St Georg Sled), with a minimum of 20 years follow-up. METHODS: Between 1974 and 1994, 399 patients (496 knees) underwent a medial fixed-bearing UKA. Prospective data were collected pre-operatively and at regular intervals post-operatively using the Bristol Knee Score (BKS), Oxford Knee (OKS) and Western Ontario MacMaster (WOMAC) scores. Kaplan-Meier survival analysis was used to determine survivorship, with revision or need for revision as end point, and differences assessed using Mantel-Cox log rank test. RESULTS: Functional knee scores improved post-operatively, but demonstrated a slight decline from 10 years of follow-up onwards. Survivorship is estimated as 86% at 10 years, 80% at 15 years, and 78% at 20 years. Sixty knees were revised, with progression of disease in another compartment the commonest reason. Eighty eight percent were revised using a primary prosthesis. For patients over the age of 65 years at the time of index procedure, 93% died with a functioning prosthesis in situ. CONCLUSION: Medial UKA demonstrates good long-term function and survivorship, and represents an excellent surgical option for patients aged over 65 years of age, where few patients will require a revision procedure. LEVEL OF EVIDENCE: IV.

Effects of Charcoal Rot on Soybean Seed Composition in Soybean Genotypes That Differ in Charcoal Rot Resistance under Irrigated and Non-Irrigated Conditions.

Charcoal rot is a major disease of soybean (Glycine max) caused by Macrophomina phaseolina and results in significant loss in yield and seed quality. The effects of charcoal rot on seed composition (seed protein, oil, and fatty acids), a component of seed quality, is not well understood. Therefore, the objective of this research was to investigate the impact of charcoal rot on seed protein, oil, and fatty acids in different soybean genotypes differing in their charcoal rot susceptibility under irrigated and non-irrigated conditions. Two field experiments were conducted in 2012 and 2013 in Jackson, TN, USA. Thirteen genotypes differing in charcoal rot resistance (moderately resistant and susceptible) were evaluated. Under non-irrigated conditions, moderately resistant genotypes showed either no change or increased protein and oleic acid but had lower linolenic acid. Under non-irrigated conditions, most of the susceptible genotypes showed lower protein and linolenic acid but higher oleic acid. Most of the moderately resistant genotypes had higher protein than susceptible genotypes under irrigated and non-irrigated conditions but lower oil than susceptible genotypes. The different responses among genotypes for protein, oil, oleic acid, and linolenic acid observed in each year may be due to both genotype tolerance to drought and environmental conditions, especially heat differences in each year (2012 was warmer than 2013). This research showed that the increases in protein and oleic acid and the decrease in linolenic acid may be a possible physiological mechanism underlying the plant's responses to the charcoal rot infection. This research further helps scientists understand the impact of irrigated and non-irrigated conditions on seed nutrition changes, using resistant and susceptible genotypes.

Identification and Confirmation of Loci Associated With Canopy Wilting in Soybean Using Genome-Wide Association Mapping.

Drought causes significant soybean [Glycine max (L.) Merr.] yield losses each year in rain-fed production systems of many regions. Genetic improvement of soybean for drought tolerance is a cost-effective approach to stabilize yield under rain-fed management. The objectives of this study were to confirm previously reported soybean loci and to identify novel loci associated with canopy wilting (CW) using a panel of 200 diverse maturity group (MG) IV accessions. These 200 accessions along with six checks were planted at six site-years using an augmented incomplete block design with three replications under irrigated and rain-fed treatments. Association mapping, using 34,680 single nucleotide polymorphisms (SNPs), identified 188 significant SNPs associated with CW that likely tagged 152 loci. This includes 87 SNPs coincident with previous studies that likely tagged 68 loci and 101 novel SNPs that likely tagged 84 loci. We also determined the ability of genomic estimated breeding values (GEBVs) from previous research studies to predict CW in different genotypes and environments. A positive relationship (P ≤ 0.05;0.37 ≤ r ≤ 0.5) was found between observed CW and GEBVs. In the vicinity of 188 significant SNPs, 183 candidate genes were identified for both coincident SNPs and novel SNPs. Among these 183 candidate genes, 57 SNPs were present within genes coding for proteins with biological functions involved in plant stress responses. These genes may be directly or indirectly associated with transpiration or water conservation. The confirmed genomic regions may be an important resource for pyramiding favorable alleles and, as candidates for genomic selection, enhancing soybean drought tolerance.

Mitochondrial DNA abnormalities provide mechanistic insight and predict reactive oxygen species-stimulating drug efficacy.

BACKGROUND: Associations between mitochondrial genetic abnormalities (variations and copy number, i.e. mtDNAcn, change) and elevated ROS have been reported in cancer compared to normal cells. Since excessive levels of ROS can trigger apoptosis, treating cancer cells with ROS-stimulating agents may enhance their death. This study aimed to investigate the link between baseline ROS levels and mitochondrial genetic abnormalities, and how mtDNA abnormalities might be used to predict cancer cells' response to ROS-stimulating therapy. METHODS: Intracellular and mitochondrial specific-ROS levels were measured using the DCFDA and MitoSOX probes, respectively, in four cancer and one non-cancerous cell lines. Cells were treated with ROS-stimulating agents (cisplatin and dequalinium) and the IC50s were determined using the MTS assay. Sanger sequencing and qPCR were conducted to screen the complete mitochondrial genome for variations and to relatively quantify mtDNAcn, respectively. Non-synonymous variations were subjected to 3-dimensional (3D) protein structural mapping and analysis. RESULTS: Our data revealed novel significant associations between the total number of variations in the mitochondrial respiratory chain (MRC) complex I and III genes, mtDNAcn, ROS levels, and ROS-associated drug response. Furthermore, functional variations in complexes I/III correlated significantly and positively with mtDNAcn, ROS levels and drug resistance, indicating they might mechanistically influence these parameters in cancer cells. CONCLUSIONS: Our findings suggest that mtDNAcn and complexes I/III functional variations have the potential to be efficient biomarkers to predict ROS-stimulating therapy efficacy in the future.

Single-cell RNA sequencing redefines the mesenchymal cell landscape of mouse endometrium.

The endometrium is a dynamic tissue that exhibits remarkable resilience to repeated episodes of differentiation, breakdown, regeneration, and remodeling. Endometrial physiology relies on a complex interplay between the stromal and epithelial compartments with the former containing a mixture of fibroblasts, vascular, and immune cells. There is evidence for rare populations of putative mesenchymal progenitor cells located in the perivascular niche of human endometrium, but the existence of an equivalent cell population in mouse is unclear. We used the Pdgfrb-BAC-eGFP transgenic reporter mouse in combination with bulk and single-cell RNA sequencing to redefine the endometrial mesenchyme. In contrast to previous reports we show that CD146 is expressed in both PDGFRß + perivascular cells and CD31 + endothelial cells. Bulk RNAseq revealed cells in the perivascular niche which express the high levels of Pdgfrb as well as genes previously identified in pericytes and/or vascular smooth muscle cells (Acta2, Myh11, Olfr78, Cspg4, Rgs4, Rgs5, Kcnj8, and Abcc9). scRNA-seq identified five subpopulations of cells including closely related pericytes/vascular smooth muscle cells and three subpopulations of fibroblasts. All three fibroblast populations were PDGFRα+/CD34 + but were distinct in their expression of Ngfr/Spon2/Angptl7 (F1), Cxcl14/Smoc2/Rgs2 (F2), and Clec3b/Col14a1/Mmp3 (F3), with potential functions in the regulation of immune responses, response to wounding, and organization of extracellular matrix, respectively. Immunohistochemistry was used to investigate the spatial distribution of these populations revealing F1/NGFR + cells in most abundance beside epithelial cells. We provide the first definitive analysis of mesenchymal cells in the adult mouse endometrium identifying five subpopulations providing a platform for comparisons between mesenchymal cells in endometrium and other adult tissues which are prone to fibrosis.

Fixed bearing, all-polyethylene tibia, lateral unicompartmental arthroplasty - A final outcome study with up to 28 year follow-up of a single implant.

BACKGROUND: Lateral unicompartmental arthroplasty (UKA) constitutes only 5-10% of all unicompartmental replacements performed. Whilst the short and medium term benefits are well documented, there remains concern regarding the higher revision rate when compared with total knee replacement. We report the long term clinical outcome and survivorship of a large series of lateral UKA. PATIENTS AND METHODS: Between 1974 and 1994, 71 patients (82 knees) underwent a lateral fixed-bearing St Georg Sled UKA. Prospective data was collected pre-operatively and at regular intervals post-operatively using the Bristol Knee Score (BKS), with later introduction of the Oxford Knee (OKS) and Western Ontario MacMaster (WOMAC) scores. Kaplan Meier survival analysis was used, with revision, or need for revision, as end point. 85% of the patients were female. No patients were lost to follow-up. RESULTS: Functional knee scores improved post-operatively up to 10 years, at which point they demonstrated a steady decline. Survivorship was 72% at 15 years, and 68% at 20 and 25 years. Nineteen knees were revised, with progression of disease in another compartment the commonest reason. There were two revisions due to implant fracture. In patients aged over 70 years at time of index procedure, 81% died with a functioning prosthesis in situ. CONCLUSION: This represents the longest follow-up of a large series of lateral UKA. Results of this early design of fixed bearing UKA demonstrate satisfactory long term survivorship. In elderly patients, further intervention is rarely required. More contemporary designs or techniques may show improved long term survivorship in time.

A National Registry Study of Patient and Renal Survival in Adult Nephrotic Syndrome.

INTRODUCTION: We aimed to determine the mortality rate, cause of death, and rate of end-stage kidney disease (ESKD) in adults with nephrotic syndrome (NS). METHODS: We conducted a national registry-based study, including all 522 adults who had a kidney biopsy for NS in Scotland in 2014-2017. We linked the Scottish Renal Registry to death certificate data. We performed survival and Cox proportional hazards analyses, accounting for competing risks of death and ESKD. We compared mortality rates with those in the age- and sex-matched general population. RESULTS: A total of 372 patients had primary NS; 150 had secondary NS. Over a median follow-up of 866 days, 110 patients (21%) died. In patients with primary NS, observed versus population 3-year mortality was 2.1% (95% CI 0.0%-4.6%) versus 0.9% (0.8%-1.0%) in patients aged <60 years and 24.9% (18.4%-30.8%) versus 9.4% (8.3%-10.5%) in those aged ≥60 years. In secondary NS, this discrepancy was 17.1% (5.6%-27.2%) versus 1.1% (0.9%-1.2%) in <60-year-olds and 49.4% (36.6%-59.7%) versus 8.1% (6.6%-9.6%) in ≥60-year-olds. In primary NS, cardiovascular causes accounted for 28% of deaths, compared with 18% in the general population. Eighty patients (15%) progressed to ESKD. Incidence of ESKD by 3 years was 8.4% (95% CI 4.9%-11.7%) in primary and 35.1% (24.3%-44.5%) in secondary NS. Early remission of proteinuria and the absence of early acute kidney injury (AKI) were associated with lower rates of death and ESKD. CONCLUSIONS: Adults with NS have high rates of death and ESKD. Cardiovascular causes account for excess mortality in primary NS.