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National HPV vaccination coverage in Japan is less than one percent of the eligible population and cervical cancer incidence and mortality are increasing. This systematic review and meta-analysis aimed to provide a comprehensive estimate of HPV genotype prevalence for Japan.English and Japanese databases were searched to March 2021 for research reporting HPV genotypes in cytology and histology samples from Japanese women. Summary estimates were calculated by disease stage from cytology only assessment - Normal, ASCUS, LSIL, HSIL and from histological assessment - CIN1, CIN2, CIN3/AIS, ICC (ICC-SCC, and ICC-ADC), and other. A random-effects meta-analysis was used to calculate summary prevalence estimates of any-HPV, high-risk (HR) and low-risk (LR) vaccine types, and vaccine genotypes (bivalent, quadrivalent, or nonavalent). This study was registered with PROSPERO: CRD42018117596.A total of 57759 women with normal cytology, 1766 ASCUS, 3764 LSIL, 2017 HSIL, 3130 CIN1, 1219 CIN2, 869 CIN3/AIS, and 4306 ICC (which included 1032 ICC-SCC, and 638 ICC-ADC) were tested for HPV. The summary estimate of any-HPV genotype in women with normal cytology was 15·6% (95% CI: 12·3-19·4) and in invasive cervical cancer (ICC) was 85·6% (80·7-89·8). The prevalence of HR-HPV was 86·0% (95% CI: 73·9-94·9) for cytological cases of HSIL, 76·9% (52·1-94·7) for histological cases of CIN3/AIS, and 75·7% (68·0-82·6) for ICC. In women with ICC, the summary prevalence of bivalent vaccine genotypes was 58·5% (95% CI: 52·1-64·9), for quadrivalent genotypes was 58·6% (52·2-64·9) and for nonavalent genotypes was 71·5% (64·9-77·6), and of ICC cases that were HPV positive over 90% of infections are nonavalent vaccine preventable. There was considerable heterogeneity in all HPV summary estimates and for ICC, this heterogeneity was not explained by variability in study design, sample type, HPV assay type, or HPV DNA detection method, although studies published in the 1990s had lower prevalence estimates of any-HPV and HR HPV genotypes.HPV prevalence is high among Japanese women. The nonavalent vaccine is likely to have the greatest impact on reducing cervical cancer incidence and mortality in Japan.

There is increasing awareness of the need for comprehensive information on potential future sea-level rise to inform adaptation planning and coastal decision-making. The IPCC Sixth Assessment Report (AR6) states that global mean sea level rise approaching 5 m by 2150, and more than 15 m by 2300, cannot be ruled out under high greenhouse gas emissions due to uncertainty in ice sheet processes. Moreover, local sea level rise may be further exacerbated through systematic changes in the climate system, such as a rapid weakening of the Atlantic Meridional Overturning Circulation (AMOC).We combine the latest United Kingdom national sea-level projections (UKCP18) with recently published projections of Antarctic ice mass loss to develop a small set of physically consistent storylines of local sea-level change that extend to 2300. The storylines span the range of uncertainty assessed by AR6 and deliver continuous sea level rise information around the UK coastline. While we focus on the UK, the methods are generic and can be readily applied to other geographic locations. Further, we consider potential changes in coastal flood hazard associated with a weakening of the AMOC using dynamical downscaling and storm surge modelling of climate model projections.

Alveolar development and repair require tight spatiotemporal regulation of numerous signalling pathways that are influenced by chemical and mechanical stimuli. Mesenchymal cells play key roles in numerous developmental processes. Transforming growth factor-β (TGFβ) is essential for alveologenesis and lung repair, and the G protein α subunits Gαq and Gα11 (Gαq/11) transmit mechanical and chemical signals to activate TGFβ in epithelial cells. To understand the role of mesenchymal Gαq/11 in lung development, we generated constitutive (Pdgfrb-Cre+/−;Gnaqfl/fl;Gna11−/−) and inducible (Pdgfrb-Cre/ERT2+/−;Gnaqfl/fl;Gna11−/−) mesenchymal Gαq/11 deleted mice. Mice with constitutive Gαq/11 gene deletion exhibited abnormal alveolar development, with suppressed myofibroblast differentiation, altered mesenchymal cell synthetic function, and reduced lung TGFβ2 deposition, as well as kidney abnormalities. Tamoxifen-induced mesenchymal Gαq/11 gene deletion in adult mice resulted in emphysema associated with reduced TGFβ2 and elastin deposition. Cyclical mechanical stretch-induced TGFβ activation required Gαq/11 signalling and serine protease activity, but was independent of integrins, suggesting an isoform-specific role for TGFβ2 in this model. These data highlight a previously undescribed mechanism of cyclical stretch-induced Gαq/11-dependent TGFβ2 signalling in mesenchymal cells, which is imperative for normal alveologenesis and maintenance of lung homeostasis.

Apolipoprotein L1 (APOL1)-associated focal segmental glomerulosclerosis (FSGS) is the dominant form of FSGS in Black individuals. There are no targeted therapies for this condition, in part because the molecular mechanisms underlying APOL1's pathogenic contribution to FSGS are incompletely understood. Studying the transcriptomic landscape of APOL1 FSGS in patient kidneys is an important way to discover genes and molecular behaviors that are unique or most relevant to the human disease. With the hypothesis that the pathology driven by the high-risk APOL1 genotype is reflected in alteration of gene expression across the glomerular transcriptome, we compared expression and co-expression profiles of 15,703 genes in 16 Black patients with FSGS at high-risk vs 14 Black patients with a low-risk APOL1 genotype. Expression data from APOL1-inducible HEK293 cells and normal human glomeruli were used to pursue genes and molecular pathways uncovered in these studies. We discovered increased expression of APOL1 and nine other significant differentially expressed genes in high-risk patients. This included stanniocalcin, which has a role in mitochondrial and calcium-related processes along with differential correlations between high- and low-risk APOL1 and metabolism pathway genes. There were similar correlations with extracellular matrix- and immune-related genes, but significant loss of co-expression of mitochondrial genes in high-risk FSGS, and an NF-κB-down regulating gene, NKIRAS1, as the most significant hub gene with strong differential correlations with NDUF family (mitochondrial respiratory genes) and immune-related (JAK-STAT) genes. Thus, differences in mitochondrial gene regulation appear to underlie many differences observed between high- and low-risk Black patients with FSGS.

More than 800 million people suffer from kidney disease, yet the mechanism of kidney dysfunction is poorly understood. In the present study, we define the genetic association with kidney function in 1.5 million individuals and identify 878 (126 new) loci. We map the genotype effect on the methylome in 443 kidneys, transcriptome in 686 samples and single-cell open chromatin in 57,229 kidney cells. Heritability analysis reveals that methylation variation explains a larger fraction of heritability than gene expression. We present a multi-stage prioritization strategy and prioritize target genes for 87% of kidney function loci. We highlight key roles of proximal tubules and metabolism in kidney function regulation. Furthermore, the causal role of SLC47A1 in kidney disease is defined in mice with genetic loss of Slc47a1 and in human individuals carrying loss-of-function variants. Our findings emphasize the key role of bulk and single-cell epigenomic information in translating genome-wide association studies into identifying causal genes, cellular origins and mechanisms of complex traits.

C-peptide declines in type 1 diabetes, although many long-duration patients retain low, but detectable levels. Histological analyses confirm that β-cells can remain following type 1 diabetes onset. We explored the trends observed in C-peptide decline in the UK Genetic Resource Investigating Diabetes (UK GRID) cohort (N = 4,079), with β-cell loss in pancreas donors from the network for Pancreatic Organ donors with Diabetes (nPOD) biobank and the Exeter Archival Diabetes Biobank (EADB) (combined N = 235), stratified by recently reported age at diagnosis endotypes (

In most high-resource countries with organized screening programs, the incidence and mortality of cervical cancer is decreasing. Recent statistics have also revealed a reduction in invasive cervical cancer incidence as a result of national vaccination programs. Paradoxically, cervical cancer incidence has increased in Japan, particularly amongst women of reproductive age. This study aimed to examine the trends in cervical cancer incidence and mortality for young and middle adult women in Japan, by analyzing trends in 10-year interval age-groups. Cervical cancer incidence for young and middle adult women (ages 20-59 years) was obtained from high-quality population-based cancer registries in three prefectures from 1985 to 2015. National cancer mortality data were obtained from published vital statistics from 1985 to 2019. Trends in crude and age-standardized rates (ASR) were analyzed using Joinpoint regression. The cervical cancer incidence trend in 20-59-year-old women combined significantly increased over the observation period. Both crude and ASR increased from 1985 to 2015 with an annual percent change (APC) of +1.6% (95% confidence interval, 1.1, 2.1) and +1.7% (1.2, 2.3), respectively. Similar increases were seen in ages 20-29, 30-39, and 40-49 years with higher APCs especially in 20s and 30s. Both crude and ASR mortality significantly increased after the early 1990s in ages 20-59 years combined. Based on the recognition that current cervical cancer control strategies in Japan have not been effective in reducing the cervical cancer burden in young and middle adults, promotion of screening and vaccination should be urgently strengthened.

The present paper presents a framework for holistic optimization of monopile foundations for a full offshore windfarm. The framework has been developed in-house at Wood Thilsted Partners and has been used for design of several full-scale wind farms including Vineyard Wind, the first commercial scale wind farm in the US. The backbone of the code is a beam finite-element based structural analysis code that performs all necessary design checks according to the governing standards. A direct coupling to various 3D FE-software packages is in place for detailed analyses of non-trivial structural details such as bolted flange connections and welded attachments. Three dimensional FE is also used for position-specific 3D soil analysis for calibration and validation of the non-linear soil-structure interaction springs serving as boundary conditions for the model. Installation and drivability assessments are similarly included in the design flow based on the beam model and validated subsequently via parameterized 3D models. Everything is integrated in a fully automated optimization framework that can perform a full optimization sweep including automatic generation of design reports and drawing material ready for certification for a full windfarm of several hundred individual positions in a few hours. Representative examples illustrate how the framework provides the possibility for conducting large scale sensitivity studies, such as diameter and clustering studies allowing for holistic cost-optimization across all positions in a windfarm.

Objectives Despite several interventions, colorectal cancer (CRC) screening uptake remains below acceptable levels in Italy. Among the potential determinants of screening uptake, only a few studies analysed the role of general practitioners (GPs). The aim was to evaluate the variation in screening uptake of the clusters of subjects assisted by single GPs. Setting Ancona province, Central Italy. Methods Cross-sectional study, including all residents aged 50–69 years, who were offered the public screening programme with biannual faecal immunochemical tests. Demographic (of all GPs) and screening data (of all eligible residents) for years 2018–2019 were collected from the official electronic datasets of the Ancona Local Health Unit. The potential predictors of acceptable screening uptake, including GP's gender, age, and number of registered subjects, were evaluated using random-effect logistic regression, with geographical area as the cluster unit. Results The final sample consisted of 332 GP clusters, including 120,178 eligible subjects. The overall province uptake was 38.0% ± 10.7%. The uptake was lower than 30% in one-fifth of the GP clusters, and higher than 45% in another fifth. At multivariable analysis, the significant predictors of uptake were younger GP age ( p = 0.010) and lower number of registered subjects ( p Conclusions The wide variation across GPs suggests they might substantially influence screening uptake, highlighting a potential need to increase their commitment to CRC screening. Further research is needed to confirm the role of the number of registered subjects.

Kidneys have one of the most complex three-dimensional cellular organizations in the body, but the spatial molecular principles of kidney health and disease are poorly understood. Here we generate high-quality single cell (sc), single nuclear (sn), spatial (sp) RNA expression and sn open chromatin datasets for 73 samples, capturing half a million cells from healthy, diabetic, and hypertensive diseased human kidneys. Combining the sn/sc and sp RNA information, we identify > 100 cell types and states and successfully map them back to their spatial locations. Computational deconvolution of spRNA-seq identifies glomerular/vascular, tubular, immune, and fibrotic spatial microenvironments (FMEs). Although injured proximal tubule cells appear to be the nidus of fibrosis, we reveal the complex, heterogenous cellular and spatial organization of human FMEs, including the highly intricate and organized immune environment. We demonstrate the clinical utility of the FME spatial gene signature for the classification of a large number of human kidneys for disease severity and prognosis. We provide a comprehensive spatially-resolved molecular roadmap for the human kidney and the fibrotic process and demonstrate the clinical utility of spatial transcriptomics.

Background Bevacizumab is a recombinant monoclonal antibody against the vascular endothelial growth factor A (VEGF-A) ligand that is used in the management of various solid malignancies. The adverse effect profiles of angiogenesis inhibitors, such as bevacizumab, have become increasingly well characterized and include renal manifestations such as hypertension, proteinuria, and thrombotic microangiopathy. Eculizumab inhibits terminal-complement activation and is used to treat atypical hemolytic uremic syndrome. There has been growing usage of eculizumab to treat bevacizumab-associated thrombotic microangiopathy. Materials and methods We performed a systematic review of the literature to identify full-text articles that describe the use of eculizumab for bevacizumab-associated thrombotic microangiopathy. Results Our systematic review identified 522 unique articles of which 5 were included in the final review. 9 cases, including 2 new cases presented in this review, were identified in which eculizumab was used in the management of bevacizumab-associated thrombotic microangiopathy. Hematologic parameters and kidney function stabilized or improved in all cases, and the 2 patients who required renal replacement therapy were able to discontinue dialysis. Conclusions Given the findings of this systematic review, the use of eculizumab in the treatment of bevacizumab-associated thrombotic microangiopathy warrants further study, particularly in severe cases.

C-peptide declines in type 1 diabetes although many long-duration patients retain low, but detectable levels. Histological analyses confirm that beta cells can remain following type 1 diabetes onset. We explored the trends observed in C-peptide decline in UK Genetic Resource Investigating Diabetes (UK GRID) cohort (N=4,079), with beta cell loss in pancreas donors from the network for Pancreatic Organ donors with Diabetes (nPOD) biobank and the Exeter Archival Diabetes Biobank (EADB) (combined N=235), stratified by recently reported age at diagnosis endotypes (< 7, 7-12, ≥ 13 years) across increasing diabetes durations. The proportion of individuals with detectable C-peptide declined beyond the first year after diagnosis, but this was most marked in the youngest age group (< 1 year duration: age < 7 years: 18/20 (90%), 7-12 years: 107/110 (97%), ≥ 13 years: 58/61 (95%) versus. 1-5 years post diagnosis: < 7 years: 172/522 (33%), 7-12 years: 604/995 (61%), ≥ 13 years: 225/289 (78%)). A similar profile was observed in beta cell loss, with those diagnosed at younger ages experiencing more rapid loss of islets containing insulin-positive (insulin+) beta cells < 1 year post diagnosis: age < 7 years: 23/26 (88%), 7-12 years: 32/33 (97%), ≥ 13 years: 22/25 (88%) versus. 1-5 years post diagnosis: < 7 years: 1/12 (8.3%) ,7-12 years: 7/13 (54%), ≥ 13 years: 7/8 (88%)). These data should be considered in the planning and interpretation of intervention trials designed to promote beta cell retention and function.

Background Microscopic analysis of urine sediment is probably the most commonly used diagnostic procedure in nephrology. The urinary cells, however, have not yet undergone careful unbiased characterization. Methods Single-cell transcriptomic analysis was performed on 17 urine samples obtained from five subjects at two different occasions, using both spot and 24-hour urine collection. A pooled urine sample from multiple healthy individuals served as a reference control. In total 23,082 cells were analyzed. Urinary cells were compared with human kidney and human bladder datasets to understand similarities and differences among the observed cell types. Results Almost all kidney cell types can be identified in urine, such as podocyte, proximal tubule, loop of Henle, and collecting duct, in addition to macrophages, lymphocytes, and bladder cells. The urinary cell-type composition was subject specific and reasonably stable using different collection methods and over time. Urinary cells clustered with kidney and bladder cells, such as urinary podocytes with kidney podocytes, and principal cells of the kidney and urine, indicating their similarities in gene expression. Conclusions A reference dataset for cells in human urine was generated. Single-cell transcriptomics enables detection and quantification of almost all types of cells in the kidney and urinary tract.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma. Currently, there is a lack of noninvasive methods to stratify ccRCC prognosis prior to any invasive therapies. The purpose of this study was to preoperatively predict the tumor stage, size, grade, and necrosis (SSIGN) score of ccRCC using MRI-based radiomics. A multicenter cohort of 364 histopathologically confirmed ccRCC patients (272 low [

Adolescent- and adult-onset disease minimal change disease (MCD) may have a clinical course distinct from childhood-onset disease. We characterized the course of children and adults with MCD in the Cure Glomerulopathy Network (CureGN) and assessed predictors of rituximab response.Prospective, multicenter, observational study.CureGN participants with proven MCD on biopsy.Age at disease onset. Initiation of RAAS blockade and immunosuppression including rituximab during the study period.Relapse and remission, change in eGFR and kidney failure.Remission and relapse probabilities are estimated using Kaplan-Meier curves and gap time recurrent event models. Linear regression models were used for the outcome of change in estimated glomerular filtration rate (eGFR). Cox proportional hazards models were used to estimate the association between rituximab administration and remission.304 childhood (≤12 years old), 49 adolescent (13-17 years old), and 201 adult onset (≥18 years) participants were included with 2.7-3.2 years of follow-up after enrollment. Children had longer time to biopsy (238 days vs. 23 in adolescents, and 36 in adults, p0.001) and were more likely to have received therapy prior to biopsy. Children were more likely to be treated with immunosuppression but not RAAS blockade. The rate of relapse was higher in childhood-onset versus adult-onset participants (hazard ratio (HR) 1.69 (95% confidence interval (CI) 1.29-2.21)). The probability of remission was also higher in childhood-onset disease (HR 1.33 (95%CI 1.02-1.72)). eGFR loss in all groups was minimal. Children were more likely to remit after rituximab than adolescents and adults (adjusted HR 2.1, p=0.003). Across all groups, glucocorticoid-sensitivity was associated with a greater likelihood of achieving complete remission after rituximab (adjusted HR 2.62, p=0.002).CureGN was limited to biopsy-proven disease. Comparisons of childhood to non-childhood cases of MCD may be subject to selection bias, given that childhood cases who are biopsied may be limited to those patients who are least responsive to initial therapy.Among patients with MCD who underwent kidney biopsy, there were differences in the course (relapse and remission) of childhood-onset compared to adolescent and adult-onset disease, as well as rituximab response.

Coding variants (named G1 and G2) in Apolipoprotein L1 (APOL1) can explain most excess risk of kidney disease observed in African American individuals. It has been proposed that risk variant APOL1 dose, such as increased risk variant APOL1 level serves as a trigger (second hit) for disease development. The goal of this study was to determine whether lowering risk variant APOL1 levels protects from disease development in a podocyte-specific transgenic mouse disease model. We administered antisense oligonucleotides (ASO) targeting APOL1 to podocyte-specific G2APOL1 mice and observed efficient reduction of APOL1 levels. APOL1 ASO1, which more efficiently lowered APOL1 transcript levels, protected mice from albuminuria, glomerulosclerosis, tubulointerstitial fibrosis, and renal failure. Administration of APOL1 ASO1 was effective even for established disease in the NEFTA-rtTA/TRE-G2APOL1 (NEFTA/G2APOL1) mice. We observed a strong correlation between APOL1 transcript level and disease severity. We concluded that APOL1 ASO1 may be an effective therapeutic approach for APOL1-associated glomerular disease.

Ocean heat content is arguably the most relevant metric for tracking the current global heating. Because of its enormous heat capacity, the global ocean stores about 89 percent of the excess heat in the Earth System. Time series of global ocean heat content (OHC) closely track Earth’s energy imbalance, observed as the net radiative imbalance at the top of the atmosphere. Therefore, simulated OHC time series are a cornerstone for assessing the scientific performance of Earth System models (ESM) and global climate models. Here we present a detailed global and regional analysis of the OHC change in CMIP6 simulations of the historical climate (20th century up to 2014) performed with four state-of-the art ESMs and climate models: UKESM1, HadGEM3-GC3.1-LL, CNRM-ESM2-1 and CNRM-CM6-1. All four share the same ocean component, NEMO3.6 in the shaconemo eORCA1 configuration. Analysing only a small number of models allows us to extend our analysis from a global perspective, to also consider individual ocean basins.For the global ocean, the two CNRM models reproduce the observed OHC change since the 1960s closely, especially in the top 700 m of the ocean. The two UK models (UKESM1 and HadGEM3-GC3.1-LL) do not simulate the observed global ocean warming in the 1970s and 1980s in the top 700 m, and they warm too fast after 1991. We analyse how this varied performance across the models relates to the simulated radiative forcing of the atmosphere and its components. All four models show a larger transient climate response (TCR) than the CMIP5 ensemble mean.For the UK models, resolving the ocean warming in depth and time shows virtually zero historical warming at intermediate depths (700 m – 2000 m) whereas the global full-depth OHC change is reasonably simulated. After 1991, regional ocean heat uptake in the North Atlantic plays a substantial role in compensating small warming rates elsewhere.A different picture emerges from the CNRM models. Globally the simulated OHC change is closer to observations, especially for CNRM-ESM2-1. Regionally the simulated OHC change is close to observations in the Pacific and Indian basins, while tending to be too small in the Atlantic, indicating a markedly different role for the Atlantic meridional overturning circulation (AMOC) and for cross-equatorial heat transport between the CNRM models and the UK models. While the UK models simulate larger than observed historical warming below 2000 m in the Atlantic and South Pacific, the CNRM models take up heat at a larger than observed rate at intermediate depths in the South Atlantic and the South Pacific, with a much smaller role for the North Atlantic in global ocean heat uptake.

The Southwest Atlantic section of the Southern Ocean is a highly energetic confluence zone where Pacific and Antarctic waters flow via the Antarctic Circumpolar Current (ACC) to merge with waters from the Atlantic Ocean and contribute to the global overturning circulation. However, there is an insufficient understanding of sub-mesoscale variability in the region. Such processes are known to play an important role in the vertical and lateral exchange of water masses, along with tracers such as carbon, atmosphere-ocean exchange, ocean productivity, and the mixing budget necessary to complete the overturning circulation. In particular, observations of the subsurface structure of frontal systems on high spatial scales are currently lacking, with typical hydrographic transects being too coarse to resolve sub-mesoscale processes and ACC filaments.Here we present the first multichannel seismic images of ocean finestructure to the north of the North Scotia Ridge in the Southern Ocean, which cross several frontal systems and bathymetric features. High-resolution (O(10m)) sections of sub-surface thermohaline structure are revealed and analysed by combining the acoustic information with hydrographic (CTD, XBT and ARGO floats), current velocity (VMADCP) and satellite altimetry data. In addition, diapycnal mixing and potential vorticity estimates are generated from acoustic data. The sections reveal an intricate and complex pattern of oceanic finestructure: very high thermohaline gradients are present in shallow and intermediate waters of up to 700 m depth associated with Subantarctic Surface Water, Subantarctic Mode water and a mix of Antarctic Intermediate Water and Antarctic Surface Water; curving features, lenses and filaments with length scales of 100m-10km are found at the Polar Front and Southern ACC front; and steep continuous gradients with separate filaments are typically present in deeper sections (up to 2000 m) associated with Circumpolar Deep Water. Furthermore, acoustic reflections provide evidence that bathymetric features like the Maurice Ewing Bank or the Northeast Georgia Rise disrupt the flow of intermediate and deep water in the region and enhance diapycnal mixing.

Robotic-assisted total knee arthroplasty (RA-TKA) has been shown to improve the accuracy of bone resection, reduce radiographic outliers, and decrease iatrogenic injury. However, it has also been shown that RA-TKA surgical times can be longer than manual surgery during adoption. The purpose of this article was to investigate (1) the characteristics of the operative time curves and trends, noting the amount of surgeons who improved, for those who performed at least 12 cases (based on initial modeling); (2) the proportion of RA surgeons who achieved the same operative times for RA-TKA as compared with manual TKAs; and (3) the number of RA-TKA cases until a steady-state operative time was achieved. TKA operative times were collected from 30 hospitals for 146 surgeons between January 1, 2016, and December 31, 2019. A hierarchical Bayesian model was used to estimate the difference between the mean RA-TKA times by case interval and the weighted baseline for manual times. The learning curve was observed at the 12th case. Therefore, operative times were analyzed for each surgeon who performed at least 12 RA-TKA cases to determine the percentage of these surgeons who trended toward a decrease or increase in their times. These surgeons were further analyzed to determine the proportion who achieved the same operating times as manual TKAs. A further hierarchical Bayesian model was used to determine when these surgeons achieved steady-state operative times. There were 60 surgeons (82%) who had decreasing surgical times over the first 12 RA-TKA cases. The remaining 13 (18%) had increasing surgical times (mean increase of 0.59 minutes/case). Approximately two-thirds of the surgeons (64%) achieved the same operating times as manual cases. The steady-state time neutrality occurred between 15 and 20 cases and beyond. This study demonstrated the learning curve for a large cohort of RA-TKAs. This model demonstrated a learning curve between 15 and 20 cases and beyond. These are important findings for this innovative technology.

Foothill deathcamas is a bulbous, perennial, native forb found throughout the western United States. Deathcamas begins growth early in the spring. The lack of alternative forages at this time can result in livestock becoming poisoned from the consumption of deathcamas. Research on herbicides for deathcamas control is limited to work from the 1950s and 1960s that identified 2,4-D as a control agent. The objective of this study was to evaluate alternative herbicide options for deathcamas control that include 2,4-D, 2,4-D + triclopyr, quinclorac, aminopyralid, imazapic, and chlorsulfuron. We also investigated the impact of plant growth stage on deathcamas control by making herbicide applications at two growth stages. One set of plots was treated with herbicides when deathcamas was in the early vegetative stage and the second set was treated at flowering. There is some evidence that stress might affect alkaloid content; therefore, we monitored alkaloid content of treated and nontreated deathcamas. Plots were established at Mt. Sterling, UT, and Mt. Pleasant, UT. Deathcamas density was reduced in 2,4-D, 2,4-D + triclopyr, and imazapic treatments 1 and 2 yr after herbicide application (P < 0.0001). Compared with the pretreatment densities, deathcamas densities(± standard error of the mean) 2 yr after herbicide application were reduced 96% ± 1.4%, 100% ± 0%, and 98% ± 0.9% for 2,4-D, 2,4-D + triclopyr, and imazapic, respectively, at the Mt. Sterling site. At the Mt. Pleasant site, deathcamas density was reduced by 84% ± 2.8% with 2,4-D alone, whereas 2,4-D + triclopyr and imazapic provided similar density reductions as observed at the Mt. Sterling site. Steroidal alkaloid concentrations did not change in herbicide-treated deathcamas at either stage of plant growth. These data indicate that 2,4-D, 2,4-D + triclopyr, and imazapic can effectively control deathcamas in the vegetative and flowering growth stages. Nomenclature: 2,4-D; 2,4-D + triclopyr; aminopyralid; chlorsulfuron; imazapic; quinclorac; foothill deathcamas, Zigadenus paniculatus (Nutt.) S. Watson

The Duffin-Schaeffer theorem is a well-known result from metric number theory, which generalises Khinchin's theorem from monotonic functions to a wider class of approximating functions. In recent years, there has been some interest in proving versions of classical theorems from Diophantine approximation in various generalised settings. In the case of number fields, there has been a version of Khinchin's theorem proven which holds for all number fields, and a version of the Duffin-Schaeffer theorem proven only in imaginary quadratic fields. In this paper, we prove a version of the Duffin-Schaeffer theorem for all number fields.

The effects of race, ethnicity, socioeconomic status (SES), and disease severity on acute care utilization in patients with glomerular disease are unknown.Prospective cohort study.1,456 adults and 768 children with biopsy-proven glomerular disease enrolled in the Cure Glomerulonephropathy (CureGN) cohort.Race and ethnicity as a participant-reported social factor.Acute care utilization defined as hospitalizations or emergency department visits.Multivariable recurrent event proportional rate models were used to estimate associations between race and ethnicity and acute care utilization.Black or Hispanic participants had lower SES and more severe glomerular disease than White or Asian participants. Acute care utilization rates were 45.6, 29.5, 25.8, and 19.2 per 100 person-years in Black, Hispanic, White, and Asian adults, respectively, and 55.8, 42.5, 40.8, and 13.0, respectively, for children. Compared with the White race (reference group), Black race was significantly associated with acute care utilization in adults (rate ratio [RR], 1.76 [95% CI, 1.37-2.27]), although this finding was attenuated after multivariable adjustment (RR, 1.31 [95% CI, 1.03-1.68]). Black race was not significantly associated with acute care utilization in children; Asian race was significantly associated with lower acute care utilization in children (RR, 0.32 [95% CI 0.14-0.70]); no significant associations between Hispanic ethnicity and acute care utilization were identified.We used proxies for SES and lacked direct information on income, household unemployment, or disability.Significant differences in acute care utilization rates were observed across racial and ethnic groups in persons with prevalent glomerular disease, although many of these difference were explained by differences in SES and disease severity. Measures to combat socioeconomic disadvantage in Black patients and to more effectively prevent and treat glomerular disease are needed to reduce disparities in acute care utilization, improve patient wellbeing, and reduce health care costs.

Background: We assessed the effectiveness of an HPV (human papillomavirus) vaccination program in lowering cervical abnormality risk, and conferring herd protection. Methods: Retrospective cohort study using linked screening and vaccination administrative health data of the general population of Ancona Province, Italy. We included all female residents born in 1990–1993, eligible for catch-up HPV vaccination up to age 25 years, and adhering to organized screening in 2015–2020 (n = 4,665). Cervical abnormalities rates were compared between: Vaccinated and unvaccinated women, and cohorts with high and low vaccination uptake. Analyses were adjusted for age, country of birth, screening tests number, laboratory, and municipality average income. Main outcomes were ASC-US+ or LSIL+ Pap smears, and CIN1+ or CIN2+ histology. Results: Mean screening age was 26.6±1.5 years, and 1,118 screened women (24.0%) were vaccinated (mean vaccination age 19.2±1.5 years). The diagnosed cervical abnormalities were: 107 LSIL+ (2.3%), 70 CIN1+ (1.5%), and 35 CIN2+ (0.8%). The adjusted odds ratios of LSIL+, CIN1+, and CIN2+ among vaccinated versus unvaccinated women were, respectively: 0.55 [(95% confidence interval (CI), 0.33–0.91)], 0.43 (95% CI, 0.22–0.86), and 0.31 (95% CI, 0.11–0.91). Among the unvaccinated, those in the highest-uptake (45.3%) 1993 cohort, versus the last pre-vaccination 1990 cohort, showed AORs of LSIL+ and CIN1+ of 0.23 (95% CI, 0.10–0.50), and 0.22 (95% CI, 0.07–0.69), respectively. Conclusions: In the first evaluation from Central Italy, catch-up HPV vaccination considerably reduced the risk of all cervical abnormalities diagnosed within organized screening, and conferred an elevated degree of herd protection among unvaccinated women. Impact: The high protection conferred by HPV vaccination suggests the need to update cervical screening.