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For prostate cancer, the role of elective nodal irradiation (ENI) for cN0 or pN0 patients has been under discussion for years. Considering the recent publications of randomized controlled trials, the prostate cancer expert panel of the German Society of Radiation Oncology (DEGRO) aimed to discuss and summarize the current literature. Modern trials have been recently published for both treatment-naïve patients (POP-RT trial) and patients after surgery (SPPORT trial). Although there are more reliable data to date, we identified several limitations currently complicating the definitions of general recommendations. For patients with cN0 (conventional or PSMA-PET staging) undergoing definitive radiotherapy, only men with high-risk factors for nodal involvement (e.g., cT3a, GS ≥ 8, PSA ≥ 20 ng/ml) seem to benefit from ENI. For biochemical relapse in the postoperative situation (pN0) and no PSMA imaging, ENI may be added to patients with risk factors according to the SPPORT trial (e.g., GS ≥ 8; PSA > 0.7 ng/ml). If PSMA-PET/CT is negative, ENI may be offered for selected men with high-risk factors as an individual treatment approach. [ABSTRACT FROM AUTHOR]

Recent advances in multiplexed single‐cell transcriptomics experiments facilitate the high‐throughput study of drug and genetic perturbations. However, an exhaustive exploration of the combinatorial perturbation space is experimentally unfeasible. Therefore, computational methods are needed to predict, interpret, and prioritize perturbations. Here, we present the compositional perturbation autoencoder (CPA), which combines the interpretability of linear models with the flexibility of deep‐learning approaches for single‐cell response modeling. CPA learns to in silico predict transcriptional perturbation response at the single‐cell level for unseen dosages, cell types, time points, and species. Using newly generated single‐cell drug combination data, we validate that CPA can predict unseen drug combinations while outperforming baseline models. Additionally, the architecture's modularity enables incorporating the chemical representation of the drugs, allowing the prediction of cellular response to completely unseen drugs. Furthermore, CPA is also applicable to genetic combinatorial screens. We demonstrate this by imputing in silico 5,329 missing combinations (97.6% of all possibilities) in a single‐cell Perturb‐seq experiment with diverse genetic interactions. We envision CPA will facilitate efficient experimental design and hypothesis generation by enabling in silico response prediction at the single‐cell level and thus accelerate therapeutic applications using single‐cell technologies. Synopsis: The compositional perturbation autoencoder (CPA) is a deep learning model for predicting the transcriptomic responses of single cells to single or combinatorial treatments from drugs and genetic manipulations. CPA can be trained on highly multiplexed, single‐cell experiments with thousands of conditions to predict unmeasured phenotypes (e.g., specific dose responses).It can generalize to predict responses to small molecules never seen in the training by adding priors on chemical space.Validations using a newly generated combinatorial drug perturbation dataset demonstrate the accuracy of CPA in predicting unseen drug combinations.CPA is also applicable to genetic combinatorial screens, as shown by imputing in silico 5,329 missing combinations in a single‐cell perturb‐seq experiment with diverse genetic interactions. [ABSTRACT FROM AUTHOR]

Purpose: To firstly examine the pain levels during distraction osteogenesis (DO) with lengthening nails (LN) in a large sample. Methods: A total of 168 cases underwent DO of the tibia or femur with five different models of LN. Under a standardized medical regime, daily pain levels were noted as nominal rating scale (NRS) score (0–10) during the distraction phase. NRS scores and several potential influence factors (LN model, bone, approach, side, age, gender) were evaluated. Results: The mean distraction length was 39.1 ± 14.4 mm. The average NRS score decreased from postoperative day 1 with 2.84 nonlinearly by 1.03 points (36.3%) over the course of 62 days to an average score of 1.81. The mean decrease during the first thirty days was 0.67(23.6%). Subgroup analysis did not reveal any influence factors. Conclusion: Pain levels during the distraction phase are overall low, continuously decreasing, and well manageable with mostly non-opioid analgesics. [ABSTRACT FROM AUTHOR]

Background: Reconstruction of the aorto-iliac segment with femoral vein (FV) as substitute for infected synthetic grafts or mycotic aneurysms constitutes the most sustainably convenient alternative. The aim of this study was to evaluate the long-term outcome of up to 16 years of follow-up, analysing the morphologic adaption of the FV with special emphasis on the distal and proximal anastomoses. Methods: We conducted a retrospective study of 22 patients with 109 computed tomography angiograms (CTAs) treated between August 2001 and January 2020 in case of aortic infection/aortitis. Morphologic changes like anastomotic dilatation/stenosis as well as changes of FV wall thickness were retrospectively analysed in pre- and postoperative CTAs. Results: Elective procedure was done in 17/22 (77%) cases, and 5/22 (23%) patients required emergent surgery. The median follow-up was 91.5 months (P25;P75 = 21;117). Cross-sectional diameter of proximal (20.38 ± 3.77 vs 22.04 ± 3.97 mm, p = 0.007) and distal anastomoses (13.05 ± 4.23 vs 14.61 ± 5.19 mm, p = 0.05) increased significantly, as well as the proximal and distal anastomotic areas (3.36 ± 1.29 vs 4.32 ± 1.63 mm2, p = 0.04 and 0.99 ± 0.48 vs 1.25 ± 0.72 mm2, p = 0.023, respectively). Venous wall thickness was significantly reduced at the anastomotic site (1.74 ± 0.46 vs 1.24 ± 0.31 mm, p = 0.001). The upper thigh diameter did not differ before and after harvesting of the FV (161.6 ± 29.1 vs. 178.2 ± 23.3 mm, p = 0.326, respectively). Conclusion: This long-term CTA follow-up study showed that the FV wall becomes thinner at the anastomotic site, and the anastomoses dilate with time without rupture. The FV is a durable conductor after replacement of the aorto-iliac segment due to aortic infection. Further CTA studies from more centres are warranted to evaluate the risk of vein rupture. [ABSTRACT FROM AUTHOR]

The collateral choice option gives the collateral posting party the opportunity to switch between different collateral currencies which is well-known to impact the asset price. Quantification of the option's value is of practical importance but remains challenging under the assumption of stochastic rates, as it is determined by an intractable distribution that requires involved approximations. Indeed, many practitioners still rely on deterministic spreads between the rates for valuation. We develop a scalable and stable stochastic model of the collateral spreads under the assumption of conditional independence. This allows for a common factor approximation that admits analytical results from which further estimators are obtained. We show that in modelling the spreads between collateral rates, a second-order model yields accurate results for the value of the collateral choice option. The model remains precise for a wide range of model parameters and is numerically efficient even for a large number of collateral currencies. [ABSTRACT FROM AUTHOR]

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Many contemporary HPC systems expose their jobs to substantial amounts of interference, leading to significant run-to-run variation. For example, application runtimes on Theta, a Cray XC40 system at Argonne National Laboratory, vary by up to 70 , caused by a mix of node-level and system-level effects, including network and file-system congestion in the presence of concurrently running jobs. This makes performance measurements generally irreproducible, heavily complicating performance analysis and modeling. On noisy systems, performance analysts usually have to repeat performance measurements several times and then apply statistics to capture trends. First, this is expensive and, second, extracting trends from a limited series of experiments is far from trivial, as the noise can follow quite irregular patterns. Attempts to learn from performance data how a program would perform under different execution configurations experience serious perturbation, resulting in models that reflect noise rather than intrinsic application behavior. On the other hand, although noise heavily influences execution time and energy consumption, it does not change the computational effort a program performs. Effort metrics that count how many operations a machine executes on behalf of a program, such as floating-point operations, the exchange of MPI messages, or file reads and writes, remain largely unaffected and—rare non-determinism set aside—reproducible. This paper addresses initial stage of an ExtraNoise project, which is aimed at revealing and tackling key questions of system noise influence on HPC applications. [ABSTRACT FROM AUTHOR]

Motivation While generative models have shown great success in sampling high-dimensional samples conditional on low-dimensional descriptors (stroke thickness in MNIST, hair color in CelebA, speaker identity in WaveNet), their generation out-of-distribution poses fundamental problems due to the difficulty of learning compact joint distribution across conditions. The canonical example of the conditional variational autoencoder (CVAE), for instance, does not explicitly relate conditions during training and, hence, has no explicit incentive of learning such a compact representation. Results We overcome the limitation of the CVAE by matching distributions across conditions using maximum mean discrepancy in the decoder layer that follows the bottleneck. This introduces a strong regularization both for reconstructing samples within the same condition and for transforming samples across conditions, resulting in much improved generalization. As this amount to solving a style-transfer problem, we refer to the model as transfer VAE (trVAE). Benchmarking trVAE on high-dimensional image and single-cell RNA-seq, we demonstrate higher robustness and higher accuracy than existing approaches. We also show qualitatively improved predictions by tackling previously problematic minority classes and multiple conditions in the context of cellular perturbation response to treatment and disease based on high-dimensional single-cell gene expression data. For generic tasks, we improve Pearson correlations of high-dimensional estimated means and variances with their ground truths from 0.89 to 0.97 and 0.75 to 0.87, respectively. We further demonstrate that trVAE learns cell-type-specific responses after perturbation and improves the prediction of most cell-type-specific genes by 65%. Availability and implementation The trVAE implementation is available via github.com/theislab/trvae. The results of this article can be reproduced via github.com/theislab/trvae_reproducibility. [ABSTRACT FROM AUTHOR]

RNA velocity has opened up new ways of studying cellular differentiation in single-cell RNA-sequencing data. It describes the rate of gene expression change for an individual gene at a given time point based on the ratio of its spliced and unspliced messenger RNA (mRNA). However, errors in velocity estimates arise if the central assumptions of a common splicing rate and the observation of the full splicing dynamics with steady-state mRNA levels are violated. Here we present scVelo, a method that overcomes these limitations by solving the full transcriptional dynamics of splicing kinetics using a likelihood-based dynamical model. This generalizes RNA velocity to systems with transient cell states, which are common in development and in response to perturbations. We apply scVelo to disentangling subpopulation kinetics in neurogenesis and pancreatic endocrinogenesis. We infer gene-specific rates of transcription, splicing and degradation, recover each cell's position in the underlying differentiation processes and detect putative driver genes. scVelo will facilitate the study of lineage decisions and gene regulation. scVelo reconstructs transient cell states and differentiation pathways from single-cell RNA-sequencing data. [ABSTRACT FROM AUTHOR]

Background: MRI detected extramural vascular invasion (mrEMVI) is a poor prognostic factor in rectal cancer patients. The objectives of this study were to assess survival outcomes in patients with and without mrEMVI and to compare the prognostic value of mrEMVI with other rectal cancer features. Methods: In a Dutch high volume rectal cancer center cohort of sixty-seven locally advanced rectal cancer patients, an independent radiologist reviewed all primary staging MRI scans. The presence of mrEMVI was correlated to tumor specific and survival outcomes. Results: 20/67 patients had mrEMVI positive rectal cancer. 55% (11/20) developed metachronous metastases, compared with 23% (11/47) in the mrEMVI negative group (OR 4.0, p = 0.01). Overall survival was also decreased with a Hazard ratio of 3.3 (p = 0.01). A multivariable logistic regression with a backward selection procedure was conducted including cT-stage, c-N-stage, extramural tumor invasion depth, mesorectal fascia involvement, distance to anorectal junction, tumor length, mrEMVI, CEA level, and synchronous metastases. After stepwise removal based on p value, only positive mrEMVI remained as a single significant predictor for metachronous metastases (OR: 4.16 , p < 0.05). Conclusion: Positive mrEMVI is a poor prognostic factor in locally advanced rectal cancer with a 4-fold increased risk of developing metachronous metastases after surgery and a worsened overall survival. mrEMVI also appeared an independent risk factor, with a stronger prediction for metachronous metastases than other MRI-detectable tumor characteristics. mrEMVI should be incorporated in all risk stratification guidelines for rectal cancer. [ABSTRACT FROM AUTHOR]

The influence of wettability on the residual fluid saturation is analyzed for homogeneous and heterogeneous porous systems. Several simulations under different wettability, flow rate, and heterogeneity conditions were carried out using a two-component lattice-Boltzmann method. The fluid flow driving force and initial conditions were imposed using a specific methodology that allows a clear distinction between the results obtained for immiscible displacement when the porous medium is initially saturated with one fluid (called primary) and when two fluids are filling the porous spaces (called secondary). The results show that the primary sweeping process is more effective when the displaced fluid is non-wetting. We observe that the heterogeneity has an important role for the whole process since it disturbs the fluid interfaces inducing the flow in the longitudinal and transversal directions, improving considerably the effectiveness of the primary displacement when compared with ideally homogeneous cases. We noted that for oil contact angles, θo, higher than a critical value, no residual oil is found. In all homogeneous cases, the critical value is 120°. The residual fluid increases proportionally to the capillary number for primary displacements, but it also depends on the system heterogeneity and wetting conditions. For secondary displacements in heterogeneous systems, the highest residual oil saturation is found for completely oil-wet conditions, with values ranging from 29% to 41% and tending to zero for all cases when θo > 120°. The initial water–oil distribution is found to be a determining factor in the amount of trapped oil after the waterflooding process. [ABSTRACT FROM AUTHOR]

The Altenberg Retable is one of the most important works of German art from the early 14th century. Composed of a shrine, a Madonna figure, and painted wings, it once adorned the high altar of the convent church in Altenberg/Lahn. The side and rear walls of the shrine were overpainted in 1609. Although conventional methods such as infrared reflectography and X‐ray radiography could not reveal the underlying medieval paint layer, we succeeded by conducting μ‐X‐Ray fluorescent studies. The latter measurements included a handheld spectrometer as well as μ‐X‐Ray fluorescent large area scanner. Nine sections of the side and rear walls were examined as well as a field on one of the wings (as a reference). In each section, spectra were recorded that comprised about 20 elements ranging from K to Bi. Maps of Ca, Fe, Co, Cu, Zn, As, Hg, and Pb were evaluated and interpreted on the basis of the results of prior color sampling analysis. By superposing several element maps, the original medieval iconographic program with its rows of standing saints could be revealed. With the help of iconographic comparison, these saints could be identified: St. Christopher in the central part of the rear wall, flanked by the 4 female saints Clare, Agnes, Dorothy, and Barbara. On the side walls, the apostles Peter and Paul, as well as the deacons Stephen and Lawrence were depicted. Discussed are not only different scenarios of usage for these images behind the altar but also the limits and possibilities of the measurement technology in this specific application. [ABSTRACT FROM AUTHOR]

Copyright of Der Nervenarzt is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The article presents a study on the health care utilization and self-treatment by specialist physicians and primary care physicians using the billing data from the Thuringian Association of Statutory Health Insurance Physicians. Other topics include the barriers preventing physicians in accessing healthcare services like worries on the lack of confidentiality among colleagues and the factors used in the study like the effects of age, sex, type of practice, and location of activity.

Copyright of Trauma und Berufskrankheit is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Motivation: The identification of heterogeneities in cell populations by utilizing single-cell technologies such as single-cell RNA-Seq, enables inference of cellular development and lineage trees. Several methods have been proposed for such inference from high-dimensional single-cell data. They typically assign each cell to a branch in a differentiation trajectory. However, they commonly assume specific geometries such as tree-like developmental hierarchies and lack statistically sound methods to decide on the number of branching events. Results: We present K-Branches, a solution to the above problem by locally fitting half-lines to single-cell data, introducing a clustering algorithm similar to K-Means. These halflines are proxies for branches in the differentiation trajectory of cells. We propose a modified version of the GAP statistic for model selection, in order to decide on the number of lines that best describe the data locally. In this manner, we identify the location and number of subgroups of cells that are associated with branching events and full differentiation, respectively. We evaluate the performance of our method on single-cell RNA-Seq data describing the differentiation of myeloid progenitors during hematopoiesis, single-cell qPCR data of mouse blastocyst development, single-cell qPCR data of human myeloid monocytic leukemia and artificial data. [ABSTRACT FROM AUTHOR]

We show that deep convolutional neural networks combined with nonlinear dimension reduction enable reconstructing biological processes based on raw image data. We demonstrate this by reconstructing the cell cycle of Jurkat cells and disease progression in diabetic retinopathy. In further analysis of Jurkat cells, we detect and separate a sub-population of dead cells in an unsupervised manner and, in classifying discrete cell cycle stages, we reach a sixfold reduction in error rate compared to a recent approach based on boosting on image features. In contrast to previous methods, deep learning based predictions are fast enough for on-the-fly analysis in an imaging flow cytometer. [ABSTRACT FROM AUTHOR]

The article discusses research which analyzed the billing data of the Thuringian Association of Statutory Health Insurance (SHI) Physicians. Topics include comparison of the utilization of SHI-insured outpatient services providing contract physicians and psychotherapists of the Kassenrztliche Vereinigung Thringen (KVT) physicians with a control group of non-physician patients residing in the KVT area, general utilization of outpatient medical services and discussion of the research findings.

We measured the isotope shift in the $$^2{\mathrm {S}}_{{1}/{2}}$$ $$\rightarrow $$ $$^2{\mathrm {P}}_{{3}/{2}}$$ (D2) transition in singly ionized calcium ions using photon recoil spectroscopy. The high accuracy of the technique enables us to compare the difference between the isotope shifts of this transition to the previously measured isotopic shifts of the $$^2{\mathrm {S}}_{{1}/{2}}$$ $$\rightarrow $$ $$^2{\mathrm {P}}_{{1}/{2}}$$ (D1) line. This so-called splitting isotope shift is extracted and exhibits a clear signature of field shift contributions. From the data, we were able to extract the small difference of the field shift coefficient and mass shifts between the two transitions with high accuracy. This J-dependence is of relativistic origin and can be used to benchmark atomic structure calculations. As a first step, we use several ab initio atomic structure calculation methods to provide more accurate values for the field shift constants and their ratio. Remarkably, the high-accuracy value for the ratio of the field shift constants extracted from the experimental data is larger than all available theoretical predictions. [ABSTRACT FROM AUTHOR]

Background and purpose Based on a tight network of stroke units ( SUs) and interventional centres, endovascular treatment of acute major intracranial vessel occlusion has been widely implemented in Austria. Documentation of all patients in the nationwide SU registry has thereby become mandatory. Methods Demographic, clinical and interventional characteristics of patients who underwent endovascular treatment for acute ischaemic stroke in 11 Austrian interventional centres between 1 October 2013 and 30 September 2014 were analysed. Results In total, 301 patients (50.5% women; median age 70.5 years; median National Institutes of Health Stroke Scale score 17) were identified.193 patients (64.1%) additionally received intravenous thrombolysis. The most frequent vessel occlusion sites were the M1 segment of the middle cerebral artery ( n = 161, 53.5%), the intracranial internal carotid artery ( n = 60, 19.9%) and the basilar artery ( n = 40, 13.3%). Stent retrievers were used in 235 patients (78.1%) and adequate reperfusion (modified Thrombolysis in Cerebral Infarction scores 2b and 3, median onset to reperfusion time 254 min) was achieved in 242 patients (81.4%). Symptomatic intracranial haemorrhage occurred in 7%. 43.8% of patients ( n = 132) had good functional outcome (modified Rankin Scale score 0-2) and the mortality rate was 20.9% ( n = 63) after 3 months. Compared to the anterior circulation, vertebrobasilar stroke patients had higher mortality. Patients with secondary hospital transportation had better outcomes after 3 months than in-house treated patients. Conclusion Our results document nationwide favourable outcome and safety rates of endovascular stroke treatment comparable to recent randomized trials. The ability to provide such data and the need to further optimize such an approach also underscore the contribution of respective registries. [ABSTRACT FROM AUTHOR]

Drosophila groom away debris and pathogens from the body using their legs in a stereotyped sequence of innate motor behaviors. Here, we investigated one aspect of the grooming repertoire by characterizing the D1 family dopamine receptor, DopR. Removal of DopR results in decreased hind leg grooming, as substantiated by quantitation of dye remaining on mutant and RNAi animals vs. controls and direct scoring of behavioral events. These data are also supported by pharmacological results that D1 receptor agonists fail to potentiate grooming behaviors in headless DopR flies. DopR protein is broadly expressed in the neuropil of the thoracic ganglion and overlaps with TH-positive dopaminergic neurons. Broad neuronal expression of dopamine receptor in mutant animals restored normal grooming behaviors. These data provide evidence for the role of DopR in potentiating hind leg grooming behaviors in the thoracic ganglion of adult Drosophila. This is a remarkable juxtaposition to the considerable role of D1 family dopamine receptors in rodent grooming, and future investigations of evolutionary relationships of circuitry may be warranted. [ABSTRACT FROM AUTHOR]

Objectives: To determine time to linkage to HIV care following diagnosis and to identify risk factors for delayed linkage.Methods: Patients newly diagnosed with HIV at sexually transmitted infections (STI) clinics in the Netherlands were followed until linkage to care. Data were collected at the time of diagnosis and at first consultation in care, including demographics, behavioural information, CD4+ counts and HIV viral load (VL) measurements. Delayed linkage to care was defined as >4 weeks between HIV diagnosis and first consultation.Results: 310 participants were included; the majority (90%) being men who have sex with men (MSM). For 259 participants (84%), a date of first consultation in care was known; median time to linkage was 9 days (range 0-435). Overall, 95 (31%) of the participants were not linked within 4 weeks of diagnosis; among them, 44 were linked late, and 51 were not linked at all by the end of study follow-up. Being young (<25 years), having non-Western ethnicity or lacking health insurance were independently associated with delayed linkage to care as well as being referred to care indirectly. Baseline CD4+ count, VL, perceived social support and stigma at diagnosis were not associated with delayed linkage. Risk behaviour and CD4+ counts declined between diagnosis and linkage to care.Conclusions: Although most newly diagnosed patients with HIV were linked to care within 4 weeks, delay was observed for one-third, with over half of them not yet linked at the end of follow-up. Vulnerable subpopulations (young, uninsured, ethnic minority) were at risk for delayed linkage. Testing those at risk is not sufficient, timely linkage to care needs to be better assured as well. [ABSTRACT FROM AUTHOR]

Objectives: To prospectively evaluate image quality (IQ) and radiation dose of dual-source cardiac computed tomography (CCTA) using different imaging protocols.Methods: CCTA was performed in 150 patients using the retrospective ECG-gated spiral technique (rECG) the prospective ECG-gated technique (pECG), or the prospective ECG-gated technique with systolic imaging and automated tube voltage selection (pECGsys). IQ was rated using a 16-segment coronary artery model. Techniques were compared for overall IQ, IQ of the large and the small coronary artery segments. Effective dose was used for comparison of radiation dose.Results: Overall IQ and IQ of the large segments showed no differences between the groups. IQ analysis of the small segments showed lowered IQ in pECGsys compared to rECG (p = 0.02), but not to pECG (p = 0.6). Effective dose did not differ significantly between rECG and pECG (p = 0.13), but was significantly lower for pECGsys (p < 0.001 vs. rECG and pECG).Conclusion: Radiation dose of dual-source CCTA in heart transplant recipients is significantly reduced by using prospective systolic scanning and automated tube voltage selection, while overall IQ and IQ of the large coronary segments are maintained. IQ appears to be lower compared to retrospective techniques with regard to small coronary segments.Key Points: • Cardiac computed tomography angiography is useful for cardiac allograft vasculopathy assessment. • Despite elevated heart rate, dose reduction in cardiac computed tomography is possible. • Prospective systolic gating and automated tube voltage selection enable 50 % dose reduction. [ABSTRACT FROM AUTHOR]

Objectives Certain non- AIDS-related diseases have been associated with immunodeficiency and HIV RNA levels in HIV-infected patients on combination antiretroviral therapy ( cART). We aimed to investigate these associations in patients not yet on cART, when potential antiretroviral-drug-related effects are absent and variation in RNA levels is greater. Methods Associations between, on the one hand, time-updated CD4 counts and plasma HIV RNA and, on the other hand, a composite non- AIDS-related endpoint, including major cardiovascular diseases, liver fibrosis/cirrhosis, and non- AIDS-related malignancies, were studied with multivariate Poisson regression models in 12 800 patients diagnosed with HIV infection from 1998 onwards while not yet treated with cART. Results During 18 646 person-years of follow-up, 203 non- AIDS-related events occurred. Compared with a CD4 count ≥ 500 cells/μL, adjusted relative risks ( RRs) for the composite endpoint were 4.71 [95% confidence interval ( CI) 2.98-7.45] for a CD4 count < 200 cells/μL, 2.06 (95% CI 1.38-3.06) for a CD4 count of 200-349 cells/μL, and 1.19 (95% CI 0.82-1.74) for a CD4 count of 350-499 cells/μL. There was no evidence for an independent association with HIV RNA. Other important covariates were age [ RR 1.40 (95% CI 1.31-1.49) per 5 years older], hepatitis B virus coinfection [ RR 5.66 (95% CI 3.87-8.28)] and hepatitis C virus coinfection [ RR 9.26 (95% CI 6.04-14.2)]. Conclusions In persons not yet receiving cART, a more severe degree of immunodeficiency rather than higher HIV RNA levels appears to be associated with an increased risk of our composite non- AIDS-related endpoint. Larger studies are needed to address these associations for individual non- AIDS-related events. [ABSTRACT FROM AUTHOR]