Infections have become the major cause of morbidity and mortality among patients with chronic lymphocytic leukemia (CLL) due to immune dysfunction and cytotoxic CLL treatment. Yet, predictive models ...for infection are missing. In this work, we develop the CLL Treatment-Infection Model (CLL-TIM) that identifies patients at risk of infection or CLL treatment within 2 years of diagnosis as validated on both internal and external cohorts. CLL-TIM is an ensemble algorithm composed of 28 machine learning algorithms based on data from 4,149 patients with CLL. The model is capable of dealing with heterogeneous data, including the high rates of missing data to be expected in the real-world setting, with a precision of 72% and a recall of 75%. To address concerns regarding the use of complex machine learning algorithms in the clinic, for each patient with CLL, CLL-TIM provides explainable predictions through uncertainty estimates and personalized risk factors.
The SMART study was a trial of intermittent use of antiretroviral therapy (ART) (drug conservation DC) versus continuous use of ART (viral suppression VS) as a strategy to reduce toxicities, ...including cardiovascular disease (CVD) risk. We studied the predictive value of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer with CVD morbidity and mortality in HIV-infected patients who were enrolled in SMART beyond other measured CVD risk factors.
A blood sample was available in 5098 participants who were enrolled in the SMART study for the measurement of IL-6, hsCRP and D-dimer. Hazard ratios (HR) with 95% CI for CVD events were estimated for each quartile (Q) for each biomarker vs the 1(st) quartile and for 1 SD higher levels. For both treatment groups combined, unadjusted and adjusted HRs were determined using Cox regression models.
There were 252 participants who had a CVD event over a median follow-up of 29 months. Adjusted HRs (95% CI) for CVD for Q4 vs Q1 were 4.65 (2.61, 8.29), 2.10 (1.40, 3.16), and 2.14 (1.38, 3.33) for IL-6, hsCRP and D-dimer, respectively. Associations were similar for the DC and VS treatment groups (interaction p-values were >0.30). The addition of the three biomarkers to a model that included baseline covariates significantly improved model fit (p<0.001). Area under the curve (AUC) estimates improved with inclusion of the three biomarkers in a model that included baseline covariates corresponding to other CVD risk factors and HIV factors (0.741 to 0.771; p<0.001 for difference).
In HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors. Further research is needed to determine whether these biomarkers can be used to improve CVD risk prediction among HIV positive individuals.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug ...conservation DC) than continuous ART (viral suppression VS).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.
Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case-control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval CI, 1.0-4.1; p = 0.05), 8.3 (95% CI, 3.3-20.8; p < 0.0001), and 12.4 (95% CI, 4.2-37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case-control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1-3.1; p = 0.02) to 1.5 (95% CI, 0.8-2.8) and 1.4 (95% CI, 0.8-2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.
IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Infective native aortic aneurysms (INAA) are aneurysms arising from infection of the aortic wall. Treatment is demanding with 5-year survival rates between 53 and 55%. The aim of our study was to ...evaluate the usefulness of
F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in the long-term monitoring of patients with proven INAA. Fifty-three PET/CT were performed in 15 patients with INAA in this single-center retrospective cohort study and retrospective analysis of prospectively collected Vascular Graft Cohort Study (VASGRA) data. Median metabolic activity (as measured by maximum standardized uptake value, SUVmax) of the aneurysms at the initial PET/CT was high (6.8 (IQR 5.7-21.8)), and lower at the last PET/CT prior to the end of antimicrobial therapy (3.9 (IQR 2.7-6.8); n = 11) as well as in the first PET/CT after the end of the treatment (3.9 (IQR 3.0-4.4);n = 6). Compared to the course of C-reactive protein alone, PET/CT provided different (> 20% difference in trend) or altering (opposed trend) information on the course of disease in at least 14 comparisons (56%) in 11 patients (73%). The one-year and five-year freedom from all-cause lethality was 92% (95% confidence interval 57%-99%). As compared to the course of C-reactive protein, PET/CT provides different and occasionally altering information in therapy control of INAA.
Abstract
Vascular graft or endograft Infections (VGEI) are rare but severe complications of vascular reconstructive surgery, and associated with significant mortality and morbidity risk. Positron ...emission tomography/computed tomography with
18
F-fluorodeoxyglucose (PET/CT) has been shown to have a high diagnostic accuracy in the detection of VGEI. In this single-center prospective cohort study, we assessed the rate and the impact on patient management of relevant unknown incidental findings in PET/CT of patients with proven or suspected VGEI, and clinical follow-up of all patients was performed. Our study results show a comparably high rate of relevant unknown incidental findings (181 in 502 examinations), with documented direct impact on patient management in 80 of 181 (44%) of all findings. PET/CT scan- and patient-based evaluation revealed impact on patient management in 76 of 502 (17%) of all PET/CT scans, and in 59 of 162 (36%) of all patients, respectively. Furthermore, PET/CT correctly identified the final diagnosis in 20 of 36 (56%) patients without VGEI. In conclusion, in proven and suspected VGEI, PET/CT detects a high rate of relevant unknown incidental findings with high impact on patient management.
Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association ...strategy, we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele human leukocyte antigen (HLA)-B*5701, whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated two genes, one of which encodes an RNA polymerase I subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents.
Epstein-Barr virus (EBV) is one of the most common viruses latently infecting humans. Little is known about the impact of human genetic variation on the large inter-individual differences observed in ...response to EBV infection. To search for a potential imprint of host genomic variation on the EBV sequence, we jointly analyzed paired viral and human genomic data from 268 HIV-coinfected individuals with CD4 + T cell count < 200/mm
and elevated EBV viremia. We hypothesized that the reactivated virus circulating in these patients could carry sequence variants acquired during primary EBV infection, thereby providing a snapshot of early adaptation to the pressure exerted on EBV by the individual immune response. We searched for associations between host and pathogen genetic variants, taking into account human and EBV population structure. Our analyses revealed significant associations between human and EBV sequence variation. Three polymorphic regions in the human genome were found to be associated with EBV variation: one at the amino acid level (BRLF1:p.Lys316Glu); and two at the gene level (burden testing of rare variants in BALF5 and BBRF1). Our findings confirm that jointly analyzing host and pathogen genomes can identify sites of genomic interactions, which could help dissect pathogenic mechanisms and suggest new therapeutic avenues.
To evaluate the diagnostic accuracy and specific imaging characteristics of positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (PET/CT), contrast enhanced CT (CE-CT), and a ...combined imaging approach (CE-PET/CT) in patients with infectious/mycotic (MAA), inflammatory (IAA), and non-infected, non-inflammatory abdominal aortic aneurysm (AAA). In this single-center retrospective cohort study, all imaging data sets of 29 consecutive patients with clinically suspected MAA or IAA were anonymised with different, reshuffled identification numbers and retrospectively and independently analysed by two experienced readers, blinded to all clinical patient data. Readers determined the presence or absence and MAA, IAA and AAA and of predefined imaging characteristics (e.g. fluid collection), and measured metabolic activity and wall thickness of all aneurysms. A multidisciplinary team of specialists served as standard of reference and re-evaluated every clinical case, considering all clinical, laboratory, microbiological, histopathological and imaging results, including all follow-up examinations. Diagnostic accuracy was higher in PET/CT as compared to CE-CT in differentiating AAA from MAA and IAA: area under the receiver operating characteristic curve (AUC-ROC) 0.81 (95% confidence intervals 0.69-0.92) and 0.63 (0.52-0.74) (P = 0.027). Specific imaging characteristics were significantly associated with different types of aneurysms (P<0.05), i.e. very high metabolic activity and dorsal sparing of metabolic activity in PET/CT and wall thickening in CE-CT were indicative for IAA; fat stranding and fluid collections in CE-CT were associated with MAA; while low metabolic acitivity and absence of wall thickening in PET/CT, and less fat stranding and absence of wall thickening in CE-CT were indicative for non-infected, non-inflammatory AAA. Specific imaging characteristics of PET/CT and CE-CT may be helpful in differentiating between MAA, IAA, and non-infected, non-inflammatory AAA.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To investigate the potential role of follow-up .sup.18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in therapy control of inoperable patients with alveolar ...echinococcosis. In this single-center retrospective cohort study, 48 PET/CT of 16 patients with confirmed alveolar echinococcosis were analysed. FDG-uptake of the most active echinococcosis manifestation was measured (i.e., maximum standardized uptake value (SUVmax) and in relation to background activity in normal liver tissue (SUVratio)) and compared to immunodiagnostic testing. For clinical patient follow-up, patient demographics, laboratory data, including E. granulosus hydatid fluid (EgHF) antibody units (AU) as well as clinical and treatment information were assessed for all patients at the time of PET/CT, and at the last recorded clinical visit. Metabolic activity of PET/CT measured in the echinococcosis manifestation was significantly correlated with EgHF AU (p < 0.001). The differences in metabolic activity of echinococcosis manifestations between two consecutive PET/CT examinations of the same patient and differences in EgHF AU in the respective time intervals displayed a significant positive correlation (p = 0.01). A trend for a more rapid decline in SUVratio liver over time was found in patients who stopped benzimidazole therapy versus patients who did not stop therapy (p = 0.059). In inoperable patients with alveolar echinococcosis, the course of metabolic activity in follow-up PET/CT is associated to the course EgHF antibody levels. Both parameters may potentially be used to evaluate the course of the disease and potentially predict the duration of benzimidazole therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to ...detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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