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Background Men and women with a migration background comprise an increasing proportion of incident human immunodeficiency virus (HIV) cases across Western Europe. Methods To characterize sources of transmission in local transmission chains, we used partial HIV consensus sequences with linked demographic and clinical data from the opt-out AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort of people with HIV in the Netherlands and identified phylogenetically and epidemiologically possible HIV transmission pairs in Amsterdam. We interpreted these in the context of estimated infection dates, and quantified population-level sources of transmission to foreign-born and Dutch-born Amsterdam men who have sex with men (MSM) within Amsterdam transmission chains. Results We estimate that Dutch-born MSM were the predominant sources of infections among all Amsterdam MSM who acquired their infection locally in 2010–2021, and among almost all foreign-born Amsterdam MSM subpopulations. Stratifying by 2-year intervals indicated time trends in transmission dynamics, with a majority of infections originating from foreign-born MSM since 2016, although uncertainty ranges remained wide. Conclusions Native-born MSM have predominantly driven HIV transmissions in Amsterdam in 2010–2021. However, in the context of rapidly declining incidence in Amsterdam, the contribution from foreign-born MSM living in Amsterdam is increasing, with some evidence that most local transmissions have been from foreign-born Amsterdam MSM since 2016. [ABSTRACT FROM AUTHOR]

Likelihood‐based methods ignoring missingness at random (MAR) produce consistent estimates provided that the whole likelihood model is correct. However, the expected information matrix (EIM) depends on the missingness mechanism. It has been shown that calculating the EIM by considering the missing data pattern as fixed (naive EIM) is incorrect under MAR, but the observed information matrix (OIM) is valid under any MAR missingness mechanism. In longitudinal studies, linear mixed models (LMMs) are routinely applied, often without any reference to missingness. However, most popular statistical packages currently provide precision measures for the fixed effects by inverting only the corresponding submatrix of the OIM (naive OIM), which is effectively equivalent to the naive EIM. In this paper, we analytically derive the correct form of the EIM of LMMs under MAR dropout to compare its differences with the naive EIM, which clarifies why the naive EIM fails under MAR. The asymptotic coverage rate of the naive EIM is numerically calculated for two parameters (population slope and slope difference between two groups) under various dropout mechanisms. The naive EIM can severely underestimate the true variance, especially when the degree of MAR dropout is high. Similar trends emerge under misspecified covariance structure, where, even the full OIM may lead to incorrect inferences and sandwich/bootstrap estimators are generally required. Results from simulation studies and application to real data led to similar conclusions. In LMMs, the full OIM should be preferred to the naive EIM/OIM, though if misspecified covariance structure is suspected, robust estimators should be used. [ABSTRACT FROM AUTHOR]

Introduction: Clinical disadvantages of initiating ART at low CD4 counts have been clearly demonstrated but whether any excess risk remains even after reaching relatively high/safe CD4 levels remains unclear. We explore whether individuals starting ART with <500 CD4 cells/μL who increased their CD4 count above this level, have, from this point onwards, similar risk of clinical progression to serious AIDS/non-AIDS events or death with individuals starting ART with ≥500 CD4 cells/μL. Methods: Data were derived from a multicenter cohort (AMACS). Adults, starting PI, NNRTI or INSTI based ART, in or after 2000 were eligible, provided they started ART with ≥500 ("High CD4") or started with CD4 <500 cells/μL but surpassed this threshold while on ART ("Low CD4"). Baseline was the date of ART initiation ("High CD4") or of first reaching 500 CD4 cells/μL ("Low CD4"). Survival analysis, allowing for competing risks, was used to explore the risk of progression to study's endpoints. Results: The study included 694 persons in the "High CD4" and 3,306 in the "Low CD4" group. Median (IQR) follow-up was 66 (36, 106) months. In total, 257 events (40 AIDS related, 217 SNAEs) were observed. Rates of progression did not differ significantly between the two groups but the subgroup of those initiating ART with <200 CD4 cells/μL had significantly higher risk of progression after baseline, compared to those in the "High CD4" group. Conclusions: Individuals starting ART with <200 cells/μL remain on increased risk even after reaching 500 CD4 cells/μL. These patients should be closely followed. [ABSTRACT FROM AUTHOR]

Recent research on antiretroviral treatment (ART) for HIV suggests that integrase strand transfer inhibitors (INSTIs) cause faster weight gain compared to other drug classes. Here, we investigated changes in body mass index (BMI) and obesity prevalence after treatment initiation and corresponding differences between drug classes. Data were derived from a large collaborative cohort in Greece. Included individuals were adults who started ART, in or after 2010, while previously ART naïve and achieved virologic response within the first year of ART. Data were analysed using mixed fractional polynomial models. INSTI regimens led to the more pronounced BMI increases, followed by boosted PI and NNRTI based regimens. Individuals with normal initial BMI are expected to gain 6 kg with an INSTI regimen compared to 4 kg with a boosted PI and less than 3 kg with a NNRTI regimen after four years of treatment. Prevalence of obesity was 5.7% at ART initiation and 12.2%, 14.2% and 18.1% after four years of treatment with NNRTIs, PIs, and INSTIs, respectively. Dolutegravir or Raltegravir were associated with marginally faster BMI increase compared to Elvitegravir. INSTIs are associated with faster weight gain. INSTIs' increased risk of treatment emergent obesity and, possibly, weight-related co-morbidities should be judged against their improved efficacy and tolerability but increased clinical attention is required. [ABSTRACT FROM AUTHOR]

Electronic health records (EHR) provide valuable resources for longitudinal studies and understanding risk factors associated with poor clinical outcomes. However, they may not contain complete follow-ups, and the missing data may not be at random since hospital discharge may depend in part on expected but unrecorded clinical outcomes that occur after patient discharge. These non-ignorable missing data requires appropriate analysis methods. Here, we are interested in measuring and analyzing individual treatment benefits of medical treatments in patients recorded in EHR databases. We present a method for predicting individual benefits that handles non-ignorable missingness due to hospital discharge. The longitudinal clinical outcome of interest is modeled simultaneously with the hospital length of stay using a joint mixed-effects model, and individual benefits are predicted through a frequentist approach: the empirical Bayesian approach. We illustrate our approach by assessing individual pain management benefits to patients who underwent spinal fusion surgery. By calculating sample percentiles of empirical Bayes predictors of individual benefits, we examine the evolution of individual benefits over time. We additionally compare these percentiles with percentiles calculated with a Monte Carlo approach. We showed that empirical Bayes predictors of individual benefits do not only allow examining benefits in specific patients but also reflect overall population trends reliably. [ABSTRACT FROM AUTHOR]

Background: Migrant populations are overrepresented among persons diagnosed with HIV in the European Union and the European Economic Area. Understanding the timing of HIV acquisition (premigration or postmigration) is crucial for developing public health interventions and for producing reliable estimates of HIV incidence and the number of people living with undiagnosed HIV infection. We summarize a recently proposed method for determining the timing of HIV acquisition and apply it to both real and simulated data. Methods: The considered method combines estimates from a mixed model, applied to data from a large seroconverters' cohort, with biomarker measurements and individual characteristics to derive probabilities of premigration HIV acquisition within a Bayesian framework. The method is applied to a subset of data from the European Surveillance System (TESSy) and simulated data. Findings: Simulation study results showed good performance with the probabilities of correctly classifying a premigration case or a postmigration case being 87.4% and 80.4%, respectively. Applying the method to TESSy data, we estimated the proportions of migrants who acquired HIV in the destination country were 31.9%, 37.1%, 45.3%, and 45.2% for those originating from Africa, Europe, Asia, and other regions, respectively. Conclusions: Although the considered method was initially developed for cases with multiple biomarkers' measurements, its performance, when applied to data where only one CD4 count per individual is available, remains satisfactory. Application of the method to TESSy data, estimated that a substantial proportion of HIV acquisition among migrants occurs in destination countries, having important implications for public health policy and programs. [ABSTRACT FROM AUTHOR]

In most HIV-positive individuals, infection time is only known to lie between the time an individual started being at risk for HIV and diagnosis time. However, a more accurate estimate of infection time is very important in certain cases. For example, one of the objectives of the Advancing Migrant Access to Health Services in Europe (aMASE) study was to determine if HIV-positive migrants, diagnosed in Europe, were infected pre- or post-migration. We propose a method to derive subject-specific estimates of unknown infection times using information from HIV biomarkers' measurements, demographic, clinical, and behavioral data. We assume that CD4 cell count (CD4) and HIV-RNA viral load trends after HIV infection follow a bivariate linear mixed model. Using post-diagnosis CD4 and viral load measurements and applying the Bayes' rule, we derived the posterior distribution of the HIV infection time, whereas the prior distribution was informed by AIDS status at diagnosis and behavioral data. Parameters of the CD4-viral load and time-to-AIDS models were estimated using data from a large study of individuals with known HIV infection times (CASCADE). Simulations showed substantial predictive ability (e.g. 84% of the infections were correctly classified as pre- or post-migration). Application to the aMASE study (n = 2009) showed that 47% of African migrants and 67% to 72% of migrants from other regions were most likely infected post-migration. Applying a Bayesian method based on bivariate modeling of CD4 and viral load, and subject-specific information, we found that the majority of HIV-positive migrants in aMASE were most likely infected after their migration to Europe. [ABSTRACT FROM AUTHOR]

Missing data are common in longitudinal studies. Likelihood‐based methods ignoring the missingness mechanism are unbiased provided missingness is at random (MAR); under not‐at‐random missingness (MNAR), joint modeling is commonly used, often as part of sensitivity analyses. In our motivating example of modeling CD4 count trajectories during untreated HIV infection, CD4 counts are mainly censored due to treatment initiation, with the nature of this mechanism remaining debatable. Here, we evaluate the bias in the disease progression marker's change over time (slope) of a specific class of joint models, termed shared‐random‐effects‐models (SREMs), under MAR drop‐out and propose an alternative SREM model. Our proposed model relates drop‐out to both the observed marker's data and the corresponding random effects, in contrast to most SREMs, which assume that the marker and the drop‐out processes are independent given the random effects. We analytically calculate the asymptotic bias in two SREMs under specific MAR drop‐out mechanisms, showing that the bias in marker's slope increases as the drop‐out probability increases. The performance of the proposed model, and other commonly used SREMs, is evaluated under specific MAR and MNAR scenarios through simulation studies. Under MAR, the proposed model yields nearly unbiased slope estimates, whereas the other SREMs yield seriously biased estimates. Under MNAR, the proposed model estimates are approximately unbiased, whereas those from the other SREMs are moderately to heavily biased, depending on the parameterization used. The examined models are also fitted to real data and results are compared/discussed in the light of our analytical and simulation‐based findings. [ABSTRACT FROM AUTHOR]

Combined Antiretroviral therapy (cART) has improved life-expectancy of people living with HIV (PLHIV) but as they age, prevalence of chronic non-AIDS related comorbidities may increase. We study the evolution of HIV-disease markers and comorbidities’ prevalence in PLHIV in Greece. Two cross-sectional analyses (2003 and 2013) on data from the AMACS cohort were performed. Comparisons were based on population average models and were repeated for subjects under follow-up at both 2003 and 2013. 2,403 PLHIV were identified in 2003 and 4,910 in 2013 (1,730 contributing for both cross-sections). Individuals in 2013 were on average older, diagnosed/treated for HIV for longer, more likely to be on cART, virologically suppressed, and with higher CD4 counts. Chronic kidney disease, dyslipidemia and hypertension prevalence increased over time. There was an increase in prescription of lipid-lowering treatment (3.5% in 2003 vs. 7.7% 2013, p<0.001). Among 220 and 879 individuals eligible for Framingham 10-year Event Risk calculation, the proportion of patients in the high-risk group (>20%) increased from 18.2% to 22.2% (p = 0.002). Increase in the prevalence of comorbidities was more pronounced in the subset of patients who were followed in both 2003 and 2013. The increased availability and uptake of cART led to significant improvements in the immuno-virological status of PLHIV in Greece, but they aged alongside an increase in prevalence of non-AIDS related comorbidities. These results highlight the need for appropriate monitoring, optimal cART selection and long-term management and prevention strategies for such comorbidities. [ABSTRACT FROM AUTHOR]

The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of ‘exhaustion’ or ‘immune checkpoint’ markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches. [ABSTRACT FROM AUTHOR]

Recovery of CD4-positive T lymphocyte count after initiation of antiretroviral therapy (ART) has been thoroughly examined among people with human immunodeficiency virus infection. However, immunological response after restart of ART following care interruption is less well studied. We compared CD4 cell-count trends before disengagement from care and after ART reinitiation. Data were obtained from the East Africa International Epidemiology Databases to Evaluate AIDS (IeDEA) Collaboration (2001–2011; n  = 62,534). CD4 cell-count trends before disengagement, during disengagement, and after ART reinitiation were simultaneously estimated through a linear mixed model with 2 subject-specific knots placed at the times of disengagement and treatment reinitiation. We also estimated CD4 trends conditional on the baseline CD4 value. A total of 10,961 patients returned to care after disengagement from care, with the median gap in care being 2.7 (interquartile range, 2.1–5.4) months. Our model showed that CD4 cell-count increases after ART reinitiation were much slower than those before disengagement. Assuming that disengagement from care occurred 12 months after ART initiation and a 3-month treatment gap, CD4 counts measured at 3 years since ART initiation would be lower by 36.5 cells/μL than those obtained under no disengagement. Given that poorer CD4 restoration is associated with increased mortality/morbidity, specific interventions targeted at better retention in care are urgently required. [ABSTRACT FROM AUTHOR]

Background: We aimed to compare rates of virologic response and CD4 changes after combination antiretroviral (cART) initiation in individuals infected with B and specific non-B HIV subtypes. Methods: Using CASCADE data we analyzed HIV-RNA and CD4 counts for persons infected ≥1996, ≥15 years of age. We used survival and longitudinal modeling to estimate probabilities of virologic response (confirmed HIV-RNA <500 c/ml), and failure (HIV-RNA>500 c/ml at 6 months or ≥1000 c/ml following response) and CD4 increase after cART initiation. Results: 2003 (1706 B, 142 CRF02_AG, 55 A, 53 C, 47 CRF01_AE) seroconverters were included in analysis. There was no evidence of subtype effect overall for response or failure (p = 0.075 and 0.317, respectively) although there was a suggestion that those infected with subtypes CRF01_AE and A responded sooner than those with subtype B infection [HR (95% CI):1.37 (1.01–1.86) and 1.29 (0.96–1.72), respectively]. Rates of CD4 increase were similar in all subtypes except subtype A, which tended to have lower initial, but faster long-term, increases. Conclusions: Virologic and immunologic response to cART was similar across all studied subtypes but statistical power was limited by the rarity of some non-B subtypes. Current antiretroviral agents seem to have similar efficacy in subtype B and most widely encountered non-B infections in high-income countries. [ABSTRACT FROM AUTHOR]

We compared CD4 changes and viral load set-point in individuals infected with different human immunodeficiency virus type 1 (HIV-1) subtypes. HIV-1 subtype significantly influences seroconversion CD4 levels and rate of decline but not viral load set point, indicating that viral genetic diversity is associated with disease progression.Background. Human immunodeficiency virus type 1 (HIV-1) subtype may influence disease progression. We compared CD4 lymphocyte cell count levels at seroconversion, decline rates and viral load set point in individuals infected with different HIV-1 subtypes.Methods. We used data from the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) collaboration, restricted to those infected since 1996, aged ≥15 years, and applied mixed effects models for CD4 cell count decline and median regression for viral load set point (mean level 6–24 months from seroconversion).Results. The analysis included 3364 seroconverters with known HIV-1 subtypes. Compared with subtype B, CD4 at seroconversion was significantly higher for subtype CRF01 and lower for subtype C. Subsequent CD4 decline was significantly slower for subtypes A and CRF02 and marginally slower for subtype C compared with B. Mean CD4 loss at 2 years of seroconversion for white men exposed through sex between men, aged 30–39 years, having seroconverted since 2006, enrolled within 6 months of seroconversion, and without acute infection was 88, 142, 100, 130, 103, and 167 cells/µL for subtypes A, B, C, CRF01_AE, CRF02_AG, and G, respectively. In adjusted analysis, median viral load set point and time to clinical AIDS/death did not differ significantly by subtype, although all subtypes, except C, tended to have lower levels compared with B.Conclusions. HIV-1 subtype significantly influences seroconversion CD4 cell levels and decline rates but not viral load set point. These findings may be helpful to HIV-positive individuals and their attending physicians in understanding disease progression. [ABSTRACT FROM PUBLISHER]

Introduction: It is unknown whether HIV treatment guidelines, based on resource-rich country cohorts, are applicable to African populations. Methods: We estimated CD4 cell loss in ART-naïve, AIDS-free individuals using mixed models allowing for random intercept and slope, and time from seroconversion to clinical AIDS, death and antiretroviral therapy (ART) initiation by survival methods. Using CASCADE data from 20 European and 3 sub-Saharan African (SSA) cohorts of heterosexually-infected individuals, aged ≥15 years, infected ≥2000, we compared estimates between non-African Europeans, Africans in Europe, and Africans in SSA. Results: Of 1,959 (913 non-Africans, 302 Europeans - African origin, 744 SSA), two-thirds were female; median age at seroconversion was 31 years. Individuals in SSA progressed faster to clinical AIDS but not to death or non-TB AIDS. They also initiated ART later than Europeans and at lower CD4 cell counts. In adjusted models, Africans (especially from Europe) had lower CD4 counts at seroconversion and slower CD4 decline than non-African Europeans. Median (95% CI) CD4 count at seroconversion for a 15-29 year old woman was 607 (588-627) (non-African European), 469 (442-497) (European - African origin) and 570 (551-589) (SSA) cells/μL with respective CD4 decline during the first 4 years of 259 (228-289), 155 (110-200), and 199 (174-224) cells/μL (p<0.01). Discussion: Despite differences in CD4 cell count evolution, death and non-TB AIDS rates were similar across study groups. It is therefore prudent to apply current ART guidelines from resource-rich countries to African populations. [ABSTRACT FROM AUTHOR]

Background. We examined differences by geographical origin (GO) in time from HIV seroconversion (SC) to AIDS, death, and initiation of antiretroviral therapy (cART). Methods. Data from HIV seroconverter cohorts in Europe, Australia and Canada (CASCADE) was used; GO was classified as: western countries (WE), North Africa and Middle East (NAME), sub-Saharan Africa (SSA), Latin America (LA), and Asia (ASIA). Differences by GO were assessed using Cox models. Administrative censoring date was 30 June 2008. Results. Of 16 941 seroconverters, 15 548 were fromWE, 158 NAME, 762 SSA, 349 LA, and 124 ASIA. We found no differences by GO in risks of AIDS (P = .99) and death (P = .12), although seroconverters from NAME (adjusted hazard ratio [aHR]: 0.57; 95% CI: 0.33-.94) and SSA (aHR: 0.74; 95% CI: 0.50-1.10) appeared to have lower mortality than WE. Chances of initiating cART differed by GO (P < .001): seroconverters from SSA were more likely to initiate cART than WE (aHR: 1.48; 95% CI: 1.26-1.74), but not after adjustment for CD4 at SC (aHR: 1.11; 95% CI: 0.88-1.40). Conclusions. In settings with universal access to healthcare, GOdoes not play a major role in HIV disease progression. [ABSTRACT FROM AUTHOR]

The article discusses the changes of the virologic and immunological response to highly active antiretroviral interruption (HAART) resumption after treatment interruption (TI) in HIV-1. Subjects who interrupted first HAART were identified using Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE). Results show that immune reconstitution after TI is poorer after first HAART.

Repeated measurements of surrogate markers are frequently used to track disease progression, but these series are often prematurely terminated due to disease progression or death. Analysing such data through standard likelihood-based approaches can yield severely biased estimates if the censoring mechanism is non-ignorable. Motivated by this problem, we have proposed the bivariate joint multivariate random effects (JMRE) model, which has shown that when correctly specified it performs well in terms of bias reduction and precision. The bivariate JMRE model is fully parametric and belongs to the class of shared parameters joint models where a survival model for the dropouts and a mixed model for the markers' evolution are linked through a multivariate normal distribution of random effects. As in every parametric model, robustness under violations of its distributional assumptions is of great importance. In this study we generated 500 simulated data sets assuming that random effects jointly follow a heavy-tailed distribution, two skewed distributions or a mixture of two normal distributions. Moreover, we generated data where level-1 errors or residuals in the survival part of the model follow a skewed distribution. Further sensitivity analysis on the effects of reduced sample size, increased level-1 variances and altered fixed effects values was also performed. We found that fixed effects estimates are almost unaffected, but their standard errors (SEs) may be underestimated especially under heavily skewed distributions. The proposed model seems robust enough, but its performance on smaller data sets or under more extreme departures of its assumptions needs further investigation. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article characterizes the magnitude and the predictors of highly active antiretroviral therapy (HAART) interruption (TI) and investigates its immunologic and virologic consequences. It is estimated that almost one in six subjects on HAART interrupts treatment by two years. There is a need for further research on why TI is higher in women.

Background Predicting cause-specific mortality among people with HIV (PWH) could facilitate targeted care to improve survival. We assessed discrimination of the Veterans Aging Cohort Study (VACS) Index 2.0 in predicting cause-specific mortality among PWH on antiretroviral therapy (ART). Methods Using Antiretroviral Therapy Cohort Collaboration data for PWH who initiated ART between 2000 and 2018, VACS Index 2.0 scores (higher scores indicate worse prognosis) were calculated around a randomly selected visit date at least 1 year after ART initiation. Missingness in VACS Index 2.0 variables was addressed through multiple imputation. Cox models estimated associations between VACS Index 2.0 and causes of death, with discrimination evaluated using Harrell's C-statistic. Absolute mortality risk was modelled using flexible parametric survival models. Results Of 59 741 PWH (mean age: 43 years; 80% male), the mean VACS Index 2.0 at baseline was 41 (range: 0–129). For 2425 deaths over 168 162 person-years follow-up (median: 2.6 years/person), AIDS (n = 455) and non–AIDS-defining cancers (n = 452) were the most common causes. Predicted 5-year mortality for PWH with a mean VACS Index 2.0 score of 38 at baseline was 1% and approximately doubled for every 10-unit increase. The 5-year all-cause mortality C-statistic was.83. Discrimination with the VACS Index 2.0 was highest for deaths resulting from AIDS (0.91), liver-related (0.91), respiratory-related (0.89), non-AIDS infections (0.87), and non–AIDS-defining cancers (0.83), and lowest for suicides/accidental deaths (0.65). Conclusions For deaths among PWH, discrimination with the VACS Index 2.0 was highest for deaths with measurable physiological causes and was lowest for suicide/accidental deaths. [ABSTRACT FROM AUTHOR]

Background/Objectives: The right-sided aortic arch (RAA) is an uncommon variation of the aortic arch (AA), characterized by the aorta crossing over the right main bronchus. In the RAA, the descending aorta can be found on either the right or left side of the spine. The current study comprises a comprehensive retrospective computed tomography angiography (CTA) investigation into the prevalence of the RAA within the Greek population. Additionally, we will conduct a systematic review and meta-analysis to elucidate both common and rare morphological variants of the RAA. This research is significant as it sheds light on the prevalence and characteristics of the RAA in a specific population, providing valuable insights for clinical practice. Methods: Two hundred CTAs were meticulously investigated for the presence of a RAA. In addition, the PubMed, Google Scholar, and Scopus online databases were thoroughly searched for studies referring to the AA morphology. The R programming language and RStudio were used for the pooled prevalence meta-analysis, while several subgroup analyses were conducted. Results: Original study: A unique case of 200 CTAs (0.5%) was identified with an uncommon morphology. The following branches emanated from the RAA under the sequence: the right subclavian artery (RSA), the right common carotid artery (RCCA), the left common carotid artery (LCCA), and the left vertebral artery (LVA) in common origin with the aberrant left subclavian artery (ALSA). The ALSA originated from a diverticulum (of Kommerell) and followed a retroesophageal course. Systematic Review and Meta-Analysis: Sixty-two studies (72,187 total cases) met the inclusion criteria. The pooled prevalence of the RAA with a mirror-image morphology was estimated at 0.07%, and the RAA with an ALSA was estimated at <0.01%. Conclusions: AA anomalies, specifically the RAA, raise clinical interest due to their coexistence with developmental heart anomalies and possible interventional complications. Congenital heart anomalies, such as the Tetralogy of Fallot and patent foramen ovale, coexisted with RAA mirror-image morphology. [ABSTRACT FROM AUTHOR]

Introduction: The continuum of care (CoC) model has been used to describe the main pillars of HIV care. This study aims to systematically review methods and elucidate gaps in the CoC analyses, especially in terms of the timing of the progression through steps, recognized nowadays as a critical parameter for an effective response to the epidemic.Methods: A PubMed and EMBASE databases search up to December 2019 resulted in 1918 articles, of which 209 were included in this review; 84 studies presented in major HIV conferences were also included. Studies that did not provide explicit definitions, modelling studies and those reporting only on metrics for subpopulations or factors affecting a CoC stage were excluded. Included articles reported results on 1 to 6 CoC stages.Results: Percentage treated and virally suppressed was reported in 78%, percentage diagnosed and retained in care in 58%, percentage linked to care in 54% and PLHIV in 36% of the articles. Information for all stages was provided in 23 studies. Only 6 articles use novel CoC estimates: One presents a dynamic CoC based on multistate analysis techniques, two base their time-to-next-stage estimates on a risk estimation method based on the cumulative incidence function, weighted for confounding and censoring and three studies estimated the HIV infection time based on mathematical modelling.Conclusion: A limited number of studies provide elaborated time analyses of the CoC. Although time analyses lack the straightforward interpretation of the cross-sectional CoC, they provide valuable insights for the timely response to the HIV epidemic. A future goal would be to develop a model that retains the simplicity of the cross-sectional CoC but also incorporates timing between stages. [ABSTRACT FROM AUTHOR]

Misspecification of the covariance structure in a linear mixed model (LMM) can lead to biased population parameters' estimates under MAR drop-out. In our motivating example of modeling CD4 cell counts during untreated HIV infection, random intercept and slope LMMs are frequently used. In this article, we evaluate the performance of LMMs with specific covariance structures, in terms of bias in the fixed effects estimates, under specific MAR drop-out mechanisms, and adopt a Bayesian model comparison criterion to discriminate between the examined approaches in real-data applications. We analytically show that using a random intercept and slope structure when the true one is more complex can lead to seriously biased estimates, with the degree of bias depending on the magnitude of the MAR drop-out. Under misspecified covariance structure, we compare in terms of induced bias the approach of adding a fractional Brownian motion (BM) process on top of random intercepts and slopes with the approach of using splines for the random effects. In general, the performance of both approaches was satisfactory, with the BM model leading to smaller bias in most cases. A simulation study is carried out to evaluate the performance of the proposed Bayesian criterion in identifying the model with the correct covariance structure. Overall, the proposed method performs better than the AIC and BIC criteria under our specific simulation setting. The models under consideration are applied to real data from the CASCADE study; the most plausible model is identified by all examined criteria. [ABSTRACT FROM AUTHOR]

Background The presence of a caroticoclinoid bar (CCB) has been implicated in both transcranial and endonasal surgery. Its morphology reflects differences in the microsurgical anatomy of the parasellar area and its manipulation during anterior or middle clinoidectomy can result in internal carotid artery injury. Although adjustment of the surgical technique according to the CCB anatomic variants is required for safe surgical access to the paraclinoid region, a review indicated the lack of a systematic assortment of reported data regarding the prevalence of the CCB. Thus, our objective was to systematically review and document the prevalence of the CCB and its anatomic variations. Methods Three databases were systematically reviewed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement through August 2018 to identify relevant studies. Results A total of 27 reports (7521 subjects or specimens, 14,449 sides) were included in the present meta-analysis. The overall pooled prevalence of the CCB was 32.6% (95% confidence interval [CI], 26.6%–38.8%) when measured in the subjects or specimens and 23.6% (95% CI, 19.7%–27.6%) when measured in each side. The overall prevalence of the CCB reported from imaging studies was 23.1% (95% CI, 8.9%–41.4%) for the subjects/specimens and 18.7% (95% CI, 12.6%–25.7%) for each side. The presence of the CCB was slightly more prevalent (P = 0.050) on the right side. Conclusions Our results showed a considerable prevalence of the CCB, with lower prevalence rates found among imaging studies. Although meticulous preoperative investigation is mandatory, surgeons treating patients with parasellar pathologic entities should always be vigilant regarding the CCB. [ABSTRACT FROM AUTHOR]

Omicron-1 COVID-19 is less invasive in the general population than previous viral variants. However, clinical course and outcome of hospitalised patients with SARS-CoV-2 pneumonia during the shift of the predominance from Delta to Omicron variants are not fully explored. During January 2022 consecutively hospitalised patients with SARS-CoV-2 pneumonia were analysed. SARS-CoV-2 variants were identified by a 2-step pre-screening protocol and randomly confirmed by whole genome sequencing analysis. Clinical, laboratory and treatment data split by type of variant were analysed along with logistic regression of factors associated to mortality. 150 patients [mean age (SD) 67.2(15.8) years, male 54%] were analysed. Compared to Delta (n = 46), Omicron-1 patients (n = 104) were older [mean age (SD): 69.5(15.4) vs 61.9(15.8) years, p = 0.007], with more comorbidities (89.4% vs 65.2%, p = 0.001), less obesity (BMI >30Kg/m2 in 24% vs 43.5%, p = 0.034) but higher vaccination rates for COVID-19 (52.9% vs 8.7%, p < 0.001). Severe pneumonia (48.7%), pulmonary embolism (4.7%), need for invasive mechanical ventilation (8%), administration of dexamethasone (76%) and 60-day mortality (22.6%) did not significantly differ. Severe SARS-CoV-2 pneumonia independently predicted mortality [OR 8.297 (CI95% 2.080–33.095), p = 0.003]. Remdesivir administration (n = 135) was protective from death both in unadjusted and adjusted models [OR 0.157 (CI95% 0.026-0.945), p = 0.043. In a COVID-19 department the severity of pneumonia that did not differ between Omicron-1 and Delta variants predicted mortality whilst remdesivir remained protective in all analyses. Death rates did not differ between SARS-CoV-2 variants. Vigilance and consistency with prevention and treatment guidelines for COVID-19 is mandatory regardless of the predominant SARS-CoV-2 variant [ABSTRACT FROM AUTHOR]

Objective. This cross-sectional study determines the impact of the pandemic lockdowns on physical activity, and evaluates the factors associated with physical activity cessation on students and personnel of eight Greek Higher Education Institutions. Materials and Methods. A total of 6,380 volunteer participants completed a survey reporting their physical activity levels and perceptions during the COVID-19 pandemic. The survey was made available through an online platform. Results. Both the conduct and intensity of physical activity were significantly reduced from the pre-pandemic era to the second lockdown (P<0.001). Walking was the most frequently selected type of physical activity, in all periods except for the second lockdown. Loss of interest (52.4%) was the main, self-reported factor for cessation of physical activity. Females had a 31% lower probability of ceasing physical activity during lockdowns. Conclusion. The conduct and intensity of physical activity decreased significantly during the pandemic. Female gender, annual checkup attendance, and specific physical activity types during the pre-pandemic era were associated with a reduction in the risk of pausing physical activity during lockdowns. Lockdowns may be implemented in future health crises, hence measures for maintaining the physical activity of the general population, such as online group sessions and support from healthcare professionals, should be prepared. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is considered the most common form of autoimmune arthritis. The disease's prevalence is around 0.5–1% worldwide, but it seems to vary among different populations. The aim of this study was to estimate the prevalence of self-reported diagnosed RA in the general adult population in Greece. The data were derived from the Greek Health Examination Survey EMENO, a population-based survey performed between 2013 and 2016. Of the 6006 participants (response rate 72%), 5884 were eligible for this study. Prevalence estimates were calculated according to the study design. Prevalence of self-reported RA was estimated to be overall 0.5% (95% CI 0.4–0.7) being approximately three times higher in women than in men (0.7% vs 0.2%, p value = 0.004). A decrease in the prevalence of RA was observed in urban areas of the country. In contrast, higher disease rates were reported in individuals with lower socioeconomic status. Multivariable regression analysis showed that gender, age, and income were related to the occurrence of the disease. Osteoporosis and thyroid disease were the two comorbidities observed at statistically significant higher rates in individuals with self-reported RA. The prevalence of self-reported RA in Greece is similar to that reported in other European countries. Gender, age, and income are the main factors related to the disease's prevalence in Greece. [ABSTRACT FROM AUTHOR]

Therefore, the true all-cause hazard function is equal to HT ht . First, we would like to thank Vonesh and Greene (2020) for their thoughtful comments on our paper examining potential bias occurring when shared random-effects models (SREMs) are applied to incomplete marker data. [Extracted from the article]

Purpose: To estimate the prevalence of the sphenoidal emissary foramina (SEF), and the effect of possible moderators on it. Methods: A systematic online literature search was conducted. The pooled prevalence with 95% confidence intervals was estimated. Outlier and influential analyses were performed. The presence of small-study effect and publication bias were evaluated. Moderator analyses were executed to investigate the effect of the specimens' continent of origin, type of study (dried skull or imaging), probing for the evaluation of SEF patency (conduction and instruments used), side dominance (bilateral or unilateral), morphometric data [SEF diameter, distances SEF–Foramen ovale (FO) and SEF–Foramen spinosum (FS)], and the methodology used for the morphometric measurements (caliper, DICOM Viewer, and image analysis software) on the estimated prevalence. Results: In total, 6,460 subjects from 26 studies were included in the meta-analysis. The overall SEF prevalence was estimated as 38.1%. The heterogeneity was high and statistically significant. No indications of publication bias and small-study effect were identified. The conducted subgroup analyses did not yield statistically significant differences in the SEF prevalence between groups, except of the type of side dominance. Both results of the univariable and multivariable regression analyses showed the association of the unilateral dominance with a decrease in the reported SEF prevalence. Conclusion: The identification of more unilateral than bilateral foramina in a given cohort is associated with a decrease in the reported crude SEF prevalence. Laterality-specific estimates should be established for a precisive estimation of the emissary foramina prevalence. [ABSTRACT FROM AUTHOR]

Despite technical advances in recent decades and a decrease in hospital mortality (<5%), pancreaticoduodenectomy (PD) is still associated with major postoperative complications, even in high-volume centers. The present study aimed to assess the effect of a modified reconstruction technique on postoperative morbidity and mortality. A cohort study of all patients (n=218) undergoing PD between January 2010 and December 2019 was performed at Attikon University Hospital (Athens, Greece). Several variables were studied, including demographic data, past medical history, perioperative parameters, tumor markers and pathology, duration of hospitalization, postoperative complications, 30-day-survival, postoperative mortality and overall survival using multivariate logistic regression and survival analysis techniques. In this cohort, 123 patients [modified PD (mPD) group] underwent a modified reconstruction after a pylorus-preserving pancreaticoduodenectomy, which consisted of gastrojejunostomy and pancreaticojejunostomy on the same loop and an isolated hepaticojejunostomy on another loop. In the standard PD (StPD) group, 95 patients underwent standard reconstruction. The median age was 67 years, ranging from 25 to 89 years. Compared with in the StPD group, the mPD group had significantly lower rates of grade B and C pancreatic fistula (4.9% vs. 28.4%), delayed gastric emptying (7.3% vs. 42.1%), postoperative hemorrhage (3.3% vs. 20%), intensive care unit admission (8.1% vs. 18.9%), overall morbidity (Clavien-Dindo grade III-V: 14.7% vs. 42.0%), perioperative mortality (4.1% vs. 14.7%), and shorter hospitalization stay (11 days vs. 20 days). However, no difference was noted regarding median survival (35 months vs. 30 months). In this single-center series, a modified reconstruction after PD appears to be associated with improved postoperative outcomes. However, further evaluation in larger multi-center trials is required. [ABSTRACT FROM AUTHOR]

Background: More than 300 cities including the city of Amsterdam in the Netherlands have joined the UNAIDS Fast- Track Cities initiative, committing to accelerate their HIV response and end the AIDS epidemic in cities by 2030. To support this commitment, we aimed to estimate the number and proportion of Amsterdam HIV infections that originated within the city, from Amsterdam residents. We also aimed to estimate the proportion of recent HIV infections during the 5- year period 2014-- 2018 in Amsterdam that remained undiagnosed. Methods: We located diagnosed HIV infections in Amsterdam using postcode data (PC4) at time of registration in the ATHENA observational HIV cohort, and used HIV sequence data to reconstruct phylogeographically distinct, partially observed Amsterdam transmission chains. Individuallevel infection times were estimated from biomarker data, and used to date the phylogenetically observed transmission chains as well as to estimate undiagnosed proportions among recent infections. A Bayesian Negative Binomial branching process model was used to estimate the number, size, and growth of the unobserved Amsterdam transmission chains from the partially observed phylogenetic data. Results: Between 1 January 2014 and 1 May 2019, there were 846 HIV diagnoses in Amsterdam residents, of whom 516 (61%) were estimated to have been infected in 2014--2018. The rate of new Amsterdam diagnoses since 2014 (104 per 100,000) remained higher than the national rates excluding Amsterdam (24 per 100,000), and in this sense Amsterdam remained a HIV hotspot in the Netherlands. An estimated 14% [12--16%] of infections in Amsterdan MSM in 2014--2018 remained undiagnosed by 1 May 2019, and 41% [35--48%] in Amsterdam heterosexuals, with variation by region of birth. An estimated 67% [60--74%] of Amsterdam MSM infections in 2014--2018 had an Amsterdam resident as source, and 56% [41--70%] in Amsterdam heterosexuals, with heterogeneity by region of birth. Of the locally acquired infections, an estimated 43% [37--49%] were in foreignborn MSM, 41% [35--47%] in Dutch- born MSM, 10% [6--18%] in foreign- born heterosexuals, and 5% [2--9%] in Dutch- born heterosexuals. We estimate the majority of Amsterdam MSM infections in 2014--2018 originated in transmission chains that pre- existed by 2014. Conclusions: This combined phylogenetic, epidemiologic, and modelling analysis in the UNAIDS Fast- Track City Amsterdam indicates that there remains considerable potential to prevent HIV infections among Amsterdam residents through city- level interventions. The burden of locally acquired infection remains concentrated in MSM, and both Dutch- born and foreign- born MSM would likely benefit most from intensified city- level interventions. Funding: This study received funding as part of the H- TEAM initiative from Aidsfonds (project number P29701). The H- TEAM initiative is being supported by Aidsfonds (grant number: 2013169, P29701, P60803), Stichting Amsterdam Dinner Foundation, Bristol- Myers Squibb International Corp. (study number: AI424- 541), Gilead Sciences Europe Ltd (grant number: PA- HIV- PREP- 16- 0024), Gilead Sciences (protocol numbers: CO- NL- 276- 4222, CO- US- 276- 1712, CO- NL- 985- 6195), and M.A.C AIDS Fund. [ABSTRACT FROM AUTHOR]

The efficacy and safety of pancreaticoduodenectomy (PD) has not been yet studied in octogenarians in Greece. The present study reviewed records of all consecutive patients that underwent PD at the 4th Surgical Department of Attikon University Hospital (Athens, Greece) between January 1st, 2010 and December 31st, 2019. Differences between two age groups (group Y <80 years; group O >80 years) were analyzed. Study endpoints were length of stay, overall morbidity, 30-day mortality and overall survival (OS). There were 198 patients in Group Y (mean age, 65 years) and 20 patients in Group O (mean age, 82 years). Octogenarians had worse American Society of Anesthesiology score (>2; 31.3 vs. 65%; P=0.018). Median stay was not significantly different between the two groups (14 days vs. 16 days; P=0.307), neither was the 30-day mortality (6.1 vs. 5.0%; P>0.99). Median OS was similar between the two groups (35 months vs. 28 months; P=0.577). In a tertiary center in Greece, morbidity and mortality rates after PD were similar between the two groups. Patients should not be denied a PD, solely based on advanced age. [ABSTRACT FROM AUTHOR]

Catheter-associated urinary tract infections (CAUTIs) are among the most common healthcare-associated infections. Urine catheters are often reservoirs of multidrug-resistant (MDR) bacteria and sources of pathogens transmission to other patients. The current study was conducted to investigate the correlation between CAUTIs, MDR bacteremia, and infection control interventions, in a tertiary-care hospital in Athens, from 2013 to 2018. The following data were analyzed per month: 1. CAUTI incidence; 2. consumption of hand hygiene disinfectants; 3. incidence of isolation of MDR carrier patients, and 4.incidence of bacteremia/1000 patient-days [total resistant a.Gram-negative: carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae; b.Gram-positive: vancomycin-resistant Enterococci and methicillin-resistant Staphylococcus aureus]. The use of scrub disinfectant solutions was associated with decreased CAUTI rate in Total Hospital Clinics (OR: 0.97, 95% CI: 0.96–0.98, p-value: <0.001) and in Adults ICU (OR: 0.79, 95% CI: 0.65–0.96, p-value:0.018) while no correlation was found with isolation rate of MDR-carrier pathogens. Interestingly, an increase in total bacteremia (OR: 0.81, 95% CI: 0.75–0.87, p-value:<0.001) or carbapenem-resistant bacteremia correlated with decreased incidence of CAUTIs (OR: 0.96, 95% CI: 0.94–0.99, p-value: 0.008). Hand hygiene measures had a robust and constant effect on infection control, reducing the incidence of CAUTIs. [ABSTRACT FROM AUTHOR]

Background: Multidrug-resistant (MDR) bacteremia is a serious health care-associated infection with significant morbidity and excess hospitalization costs. Our aim is to study the association between incidences of MDR bacteremia, antibiotic consumption, and infection control measures in a hospital from 2013 to 2018. Methods: We analyzed the following indices: (1) incidence of bacteremia (carbapenem-resistant Acinetobacter baumanii, Pseudomonas aeruginosa, and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci); (2) use of antibiotics; (3) consumption of disinfectant solutions for hand hygiene; and (4) isolation rates of MDR carrier patients. Findings: The use of advanced antibiotics (p = 0.001) and carbapenems (p = 0.008) decreased significantly in all hospital departments but the incidence of total MDR bacteremia did not change significantly. Increased use of hand disinfectant solutions was statistically associated with decreased incidence of total MDR bacteremia (incidence rate ratio [IRR]: 0.94, confidence interval [95% CI]: 0.90–0.99, p: 0.020) in all hospital. Also, increased isolation rates of MDR carrier patients 2 months before correlated with decreased incidence of bacteremia due to carbapenem-resistant gram-negative pathogens (IRR: 0.35, 95% CI: 0.18–0.66, p: 0.001) in adults intensive care unit. Conclusion: In our hospital, hand hygiene and isolation of MDR carrier patients controlled MDR bacteremia. [ABSTRACT FROM AUTHOR]

Background: Diode-assisted endodontics is nowadays utilized for pulp space disinfection, but little is known on the bonding potential of this lased root dentin when the tooth is restored with an intracanal polymer post. Objectives: to investigate the influence of diode laser irradiation settings, in laser-assisted endodontics, on the intraradicular bonding of composite materials. Methods: Sixteen two-rooted, maxillary first premolars were collected, prepared up to F4 (Protaper Universal. Dentsply-Maillefer, Ballaigues, Switzerland), and randomly assigned in two groups: group A (chopped mode or short pulse), diode irradiated according to protocol, pulse 25 ms, power 2.5 W, and group B (microchopped mode or ultrashort pulse), pulse 25 μs, peak power 12 W (both groups GentleRay. KaVo Dental, Biberach an der Riss, Germany). Buccal canals were irradiated, palatal ones served as controls. Canals were then obturated, post space was created in all canals, and quartz-fiber posts (ICE light Danville. Danville Materials, San Ramon, CA, USA) were cemented by self-etch self-curing cement (Max Cem Elite. Kerr, West Collins Orange, CA, USA) (Max Cem Elite. Kerr, Brea, CA, USA). A week later, teeth were sectioned horizontally in 1 mm increments. Push-out test was conducted in a Zwick testing machine (Zwick Roell, Ulm, Germany) at 1 mm/min speed, and the force required to dislodge the post from each specimen (F-max) was recorded. Weibull regression models were applied for statistical analyses. Results: Differences in F-max by group (control vs. chopped mode vs. microchopped mode) and height (meaning the apical-to-coronal position of each specimen along the root) were statistically significant (p < 0.05 in all cases). Conclusions: Short pulses (or chopped mode) had a profound positive effect on the quality of intraradicular bonding, while Ultrashort pulses (or microchopped mode) affected it negatively. In addition, apically positioned bonding proved weaker compared with more coronally located specimens. [ABSTRACT FROM AUTHOR]

Introduction: Model‐based estimates of key HIV indicators depend on past epidemic trends that are derived based on assumptions about HIV disease progression and mortality in the absence of antiretroviral treatment (ART). Population‐based HIV Impact Assessment (PHIA) household surveys conducted between 2015 and 2018 found substantial numbers of respondents living with untreated HIV infection. CD4 cell counts measured in these individuals provide novel information to estimate HIV disease progression and mortality rates off ART. Methods: We used Bayesian multi‐parameter evidence synthesis to combine data on (1) cross‐sectional CD4 cell counts among untreated adults living with HIV from 10 PHIA surveys, (2) survival after HIV seroconversion in East African seroconverter cohorts, (3) post‐seroconversion CD4 counts and (4) mortality rates by CD4 count predominantly from European, North American and Australian seroconverter cohorts. We used incremental mixture importance sampling to estimate HIV natural history and ART uptake parameters used in the Spectrum software. We validated modelled trends in CD4 count at ART initiation against ART initiator cohorts in sub‐Saharan Africa. Results: Median untreated HIV survival decreased with increasing age at seroconversion, from 12.5 years [95% credible interval (CrI): 12.1–12.7] at ages 15–24 to 7.2 years (95% CrI: 7.1–7.7) at ages 45–54. Older age was associated with lower initial CD4 counts, faster CD4 count decline and higher HIV‐related mortality rates. Our estimates suggested a weaker association between ART uptake and HIV‐related mortality rates than previously assumed in Spectrum. Modelled CD4 counts in untreated people living with HIV matched recent household survey data well, though some intercountry variation in frequencies of CD4 counts above 500 cells/mm3 was not explained. Trends in CD4 counts at ART initiation were comparable to data from ART initiator cohorts. An alternate model that stratified progression and mortality rates by sex did not improve model fit appreciably. Conclusions: Synthesis of multiple data sources results in similar overall survival as previous Spectrum parameter assumptions but implies more rapid progression and longer survival in lower CD4 categories. New natural history parameter values improve consistency of model estimates with recent cross‐sectional CD4 data and trends in CD4 counts at ART initiation. [ABSTRACT FROM AUTHOR]

Introduction: Model‐based estimates of key HIV indicators depend on past epidemic trends that are derived based on assumptions about HIV disease progression and mortality in the absence of antiretroviral treatment (ART). Population‐based HIV Impact Assessment (PHIA) household surveys conducted between 2015 and 2018 found substantial numbers of respondents living with untreated HIV infection. CD4 cell counts measured in these individuals provide novel information to estimate HIV disease progression and mortality rates off ART. Methods: We used Bayesian multi‐parameter evidence synthesis to combine data on (1) cross‐sectional CD4 cell counts among untreated adults living with HIV from 10 PHIA surveys, (2) survival after HIV seroconversion in East African seroconverter cohorts, (3) post‐seroconversion CD4 counts and (4) mortality rates by CD4 count predominantly from European, North American and Australian seroconverter cohorts. We used incremental mixture importance sampling to estimate HIV natural history and ART uptake parameters used in the Spectrum software. We validated modelled trends in CD4 count at ART initiation against ART initiator cohorts in sub‐Saharan Africa. Results: Median untreated HIV survival decreased with increasing age at seroconversion, from 12.5 years [95% credible interval (CrI): 12.1–12.7] at ages 15–24 to 7.2 years (95% CrI: 7.1–7.7) at ages 45–54. Older age was associated with lower initial CD4 counts, faster CD4 count decline and higher HIV‐related mortality rates. Our estimates suggested a weaker association between ART uptake and HIV‐related mortality rates than previously assumed in Spectrum. Modelled CD4 counts in untreated people living with HIV matched recent household survey data well, though some intercountry variation in frequencies of CD4 counts above 500 cells/mm3 was not explained. Trends in CD4 counts at ART initiation were comparable to data from ART initiator cohorts. An alternate model that stratified progression and mortality rates by sex did not improve model fit appreciably. Conclusions: Synthesis of multiple data sources results in similar overall survival as previous Spectrum parameter assumptions but implies more rapid progression and longer survival in lower CD4 categories. New natural history parameter values improve consistency of model estimates with recent cross‐sectional CD4 data and trends in CD4 counts at ART initiation. [ABSTRACT FROM AUTHOR]

Highlights • Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative prosthetic joint infections (PJIs) studied. • Pseudomonas aeruginosa predominated in XDR cases, which demonstrated the worst outcome. • Colistin was unfavourable in MDR cases and should be preserved only for XDR cases. • Non-DAIR is more successful than DAIR both in early and late PJI. • Non-DAIR superiority is independent of MDR/XDR status and use of colistin. ABSTRACT Factors influencing treatment outcome of patients with Gram-negative bacterial (GNB) multidrug-resistant (MDR) and extensively drug-resistant (XDR) prosthetic joint infection (PJIs) were analysed. Data were collected (2000–2015) by 18 centres. Treatment success was analysed by surgery type for PJI, resistance (MDR/XDR) and antimicrobials (colistin/non-colistin) using logistic regression and survival analyses. A total of 131 patients (mean age 73.0 years, 35.9% male, 58.8% with co-morbidities) with MDR (n = 108) or XDR (n = 23) GNB PJI were assessed. The most common pathogens were Escherichia coli (33.6%), Pseudomonas aeruginosa (25.2%), Klebsiella pneumoniae (21.4%) and Enterobacter cloacae (17.6%). Pseudomonas aeruginosa predominated in XDR cases. Isolates were carbapenem-resistant (n = 12), fluoroquinolone-resistant (n = 63) and ESBL-producers (n = 94). Treatment outcome was worse in XDR versus MDR cases (P = 0.018). Success rates did not differ for colistin versus non-colistin in XDR cases (P = 0.657), but colistin was less successful in MDR cases (P = 0.018). Debridement, antibiotics and implant retention (DAIR) (n = 67) was associated with higher failure rates versus non-DAIR (n = 64) (OR = 3.57, 95% CI 1.68–7.58; P < 0.001). Superiority of non-DAIR was confirmed by Kaplan–Meir analysis (HR = 0.36, 95% CI 0.20–0.67) and remained unchangeable by time of infection (early/late), antimicrobial resistance (MDR/XDR) and antimicrobials (colistin/non-colistin) (Breslow–Day, P = 0.737). DAIR is associated with higher failure rates even in early MDR/XDR GNB PJIs versus implant removal. Colistin should be preserved for XDR cases as it is detrimental in MDR infections. [ABSTRACT FROM AUTHOR]

Background Despite therapeutic advancements, gastric cancer (GC) remains a leading cause of death worldwide. Methods This retrospective cohort study statistically analyzed the clinicopathologic characteristics, treatments and outcomes of patients with potentially resectable GC managed at our institution between 2006 and 2010. The STROBE checklist was applied. Results Preoperative assessment of 164 GC patients (male: female ratio 1.87, median age 65 years) assigned 132 (80.5%) to total (56; 42.4%) or subtotal (76; 57.6%) gastrectomy. Resection margins were microscopically tumor-free (R0) in 100 (75.8%), microscopically infiltrated (R1) in 25 (18.9%) and macroscopically infiltrated (R2) in 7 (5.3%) patients. Nodal plane dissection was D0 in 34 (25.8%), D1 in 62 (47.0%) and D2 in 36 (27.3%) patients. Early GC was diagnosed in 19 patients (14.4%). Fluorouracil-based chemotherapy was administered in 69.7% and chemoradiation in 18.2% of patients. The 5- and 10-year survival rates of patients with R0 resection were 74% and 65.4%, respectively. The 2-year survival rates for R1 and R2 resection were 28.9% and 0% respectively. The 5- and 10-year survival rates according to nodal plane dissection were 55.6% and 41.4% for D2, and 53.2% and 49.7% for D1, respectively. On multivariate analysis, T4, N3 and R1/R2 remained independent negative prognostic factors for overall survival. Microscopic or macroscopic infiltration of surgical margins was the worst adverse prognostic factor for survival. Conclusion These results are equivalent to those from centers of excellence and indicate the urgent need for improvements in the field, particularly in the development of predictive models to guide personalized therapy. [ABSTRACT FROM AUTHOR]

Background: Clinical guidelines recommend immediate initiation of combined antiretroviral therapy for all HIV-positive individuals. However, those guidelines are based on trials of relatively young participants. Methods: We included HIV-positive antiretroviral therapy--naive, AIDS-free individuals aged 50-70 years after 2004 in the HIV-CAUSAL Collaboration. We used the parametric g-formula to estimate the 5-year risk of all-cause and non-AIDS mortality under (1) immediate initiation at baseline and initiation at CD4 count, (2) <500 cells/mm³, and(3) <350 cells/mm³. Results were presented separately for the general HIV population and for a US Veterans cohort with high mortality. Results: The study included 9596 individuals (28% US Veterans) with median (interquantile range) age of 55 (52-60) years and CD4 count of 336 (182-513) at baseline. The 5-year risk of all-cause mortality was 0.40% (95% confidence interval (CI): 0.10 to 0.71) lower for the general HIV population and 1.61% (95% CI: 0.79 to 2.67) lower for US Veterans when comparing immediate initiation vs initiation at CD4 <350 cells/mm³. The 5-year risk of non-AIDS mortality was 0.17% (95% CI: -0.07 to 0.43) lower for the general HIV population and 1% (95% CI: 0.31 to 2.00) lower for US Veterans when comparing immediate initiation vs initiation at CD4 <350 cells/mm³. Conclusions: Immediate initiation seems to reduce all-cause and non-AIDS mortality in patients aged 50-70 years. [ABSTRACT FROM AUTHOR]

Background: Improving the effectiveness and efficiency of research informed consent is a high priority. Some express concern about longer, more complex, written consent forms creating barriers to participant understanding. A recent meta-analysis concluded that randomized comparisons were needed. Methods: We conducted a cluster-randomized non-inferiority comparison of a standard versus concise consent form within a multinational trial studying the timing of starting antiretroviral therapy in HIV+ adults (START). Interested sites were randomized to standard or concise consent forms for all individuals signing START consent. Participants completed a survey measuring comprehension of study information and satisfaction with the consent process. Site personnel reported usual site consent practices. The primary outcome was comprehension of the purpose of randomization (pre-specified 7.5% non-inferiority margin). Results: 77 sites (2429 participants) were randomly allocated to use standard consent and 77 sites (2000 participants) concise consent, for an evaluable cohort of 4229. Site and participant characteristics were similar for the two groups. The concise consent was non-inferior to the standard consent on comprehension of randomization (80.2% versus 82%, site adjusted difference: 0.75% (95% CI -3.8%, +5.2%)); and the two groups did not differ significantly on total comprehension score, satisfaction, or voluntariness (p>0.1). Certain independent factors, such as education, influenced comprehension and satisfaction but not differences between consent groups. Conclusions: An easier to read, more concise consent form neither hindered nor improved comprehension of study information nor satisfaction with the consent process among a large number of participants. This supports continued efforts to make consent forms more efficient. Trial registration: Informed consent substudy was registered as part of START study in clinicaltrials.gov #, and EudraCT # 2008-006439-12 [ABSTRACT FROM AUTHOR]

Introduction: The incidence and prevalence of HIV infection are important measures of HIV trends; however, they are difficult to estimate because of the long incubation period between infection and symptom development and the relative infrequency of HIV screening. A new method is introduced to estimate HIV incidence, prevalence, and the number of undiagnosed infections in the United States using data from the HIV case surveillance system and CD4 test results. Methods: Persons with HIV diagnosed during 2006-2013 and their CD4 test results were used to estimate the distribution of diagnosis delay from HIV infection to diagnosis based on a well-characterized CD4 depletion model. This distribution was then used to estimate HIV incidence, prevalence, and the number of undiagnosed infections. Results: Applying this method, we estimated that the annual number of new HIV infections decreased after 2007, from 48,300 (95% confidence interval [CI]: 47,300 to 49,400) to 39,000 (95% CI: 36,600 to 41,400) in 2013. Prevalence increased from 923,200 (95% CI: 914,500 to 931,800) in 2006 to 1,104,600 (95% CI: 1,084,300 to 1,124,900) in 2013, whereas the proportion of undiagnosed infections decreased from 21.0% in 2006 (95% CI: 20.2% to 21.7%) to 16.4% (95% CI: 15.7% to 17.2%) in 2013. Conclusions: HIV incidence, prevalence, and undiagnosed infections can be estimated using HIV case surveillance data and information on first CD4 test result after diagnosis. Similar to earlier findings, the decreases in incidence and undiagnosed infections are encouraging but intensified efforts for HIV testing and treatment are needed to meet the goals of the National HIV/AIDS Strategy. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the possible effect of recalled traumatic experiences, perceived parental rearing styles, and family parameters on the occurrence of borderline personality disorder (BPD) versus other personality disorders (other-PDs). A total of 88 adult outpatients with personality disorders completed the Traumatic Antecedents Questionnaire and the Egna Minnen av Barndoms Uppfostran, which measures perceptions regarding parental rearing. Results indicated that incidence of traumatic childhood experiences was higher among those in the BPD group compared to those in the other-PD group. Firstborns were less likely to carry a diagnosis of BPD over other-PDs. Also, significantly more BPD compared to other-PD patients reported being the father's favorite child over siblings. Results suggest that traumatic experiences, birth order, and family interactions in the presence of siblings seem to differentially affect the formation of borderline diagnosis compared to other-PDs. Limitations and clinical implications of the study are discussed in detail. [ABSTRACT FROM AUTHOR]

Background. Recent updates of human immunodeficiency virus (HIV) treatment guidelines have raised the CD4+ cell count thresholds for antiretroviral therapy initiation from 350 to 500 cells/mm3 in the United States and from 200 to 350 cells/mm3 in mid- and low-income countries. Robust data of time from HIV seroconversion to CD4+ cell counts of 200, 350, and 500 cells/mm3 are lacking but are needed to inform health care planners of the likely impact and cost effectiveness of these and possible future changes in CD4+ cell count initiation threshold. Methods. Using Concerted Action on Seroconversion to AIDS and Death in Europe data from individuals with well-estimated dates of HIV seroconversion, we fitted mixed models on the square root of CD+ cell counts measured before combined antiretroviral therapy (cART) initiation. Restricting analyses to adults (age >16 years), we predicted time between seroconversion and CD4+ cell count <200,<350, and<500 cells/mm3 as well as CD4+ cell count distribution and proportions reaching these thresholds at 1, 2, and 5 years after seroconversion. Results. Median (interquartile range [IQR]) follow-up for the 18 495 eligible individuals from seroconversion while cART-free was 3.7 years (1.5, 7). Most of the subjects were male (78%), had a median age at seroconversion of 30 years (IQR, 25-37 years), and were infected through sex between men (55%). Estimated median times (95% confidence interval [CI]) from seroconversion to CD4+ cell count <500, <350, and <200 cells/mm3 were 1.19 (95% CI, 1.12-1.26), 4.19 (95% CI, 4.09-4.28), and 7.93 (95% CI, 7.76-8.09) years, respectively. Almost half of infected individuals would require treatment within 1 year of seroconversion for guidelines recommending its initiation at 500 cells/mm3, compared with 26% and 9% for guidelines recommending initiation at 350 and 200 cells/mm3, respectively. Conclusions. These data suggest substantial increases in the number of individuals who require treatment and call for early HIV testing. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the serum levels of soluble markers reflecting different aspects of immune activation in HIV-1-infected patients, and assess their prognostic significance for occurrence of AIDS-related death before the advent of the highly active antiretroviral treatment (HAART). Serum concentrations of the soluble forms of interleukin-2 receptors (sIL-2R), intercellular adhesion molecule-1 (sICAM-1), and E-selectin (sEs) have been determined in a cohort of 64 HIV-1-infected patients, between 1990-1993. The patients were followed prospectively with regular visits at the outpatient department. Follow-up time was censored at January 1, 1997, the date after which HAART was introduced. The median follow-up time was 46 months (range, 2-78 months). By the end of follow-up, 34 subjects had died. Baseline levels of all three soluble markers were significantly lower in subjects who remained alive during the follow-up compared to subjects who died. Univariate analysis showed that individual sIL-2R and sICAM-1, but not sEs measurements, were significantly associated with time to death (p = 0.008 and 0.003, respectively). Even after adjustment for age and CD4[sup +] T-cell counts sIL-2R measurements remained significantly prognostic. Sensitivity analysis using follow-up time to year 2000 confirmed these results. Our data suggest that assessment of the immune activation status using the easily measured levels of circulating markers may provide additional information about the risk of AIDS-related death. Further studies are needed to assess the effect of HAART on the levels of immune activation markers and their prognostic value. [ABSTRACT FROM AUTHOR]

Reports on a study to compare results of randomized and nonrandomized studies that evaluated medical interventions and to examine characteristics that may explain discrepancies between the studies. Context; Objectives; Data sources; Study selection; Data extraction; Data Synthesis; Conclusions.

Background: Knowledge of HIV-1 molecular transmission clusters (MTCs) is important, especially in large-scale datasets, for designing prevention programmes and public health intervention strategies. We used a large-scale HIV-1 sequence dataset from nine European HIV cohorts and one Canadian, to identify MTCs and investigate factors associated with the probability of belonging to MTCs.Methods: To identify MTCs, we applied maximum likelihood inferences on partial pol sequences from 8955 HIV-positive individuals linked to demographic and clinical data. MTCs were defined using two different criteria: clusters with bootstrap support >75% (phylogenetic confidence criterion) and clusters consisting of sequences from a specific region at a proportion of >75% (geographic criterion) compared to the total number of sequences within the network. Multivariable logistic regression analysis was used to assess factors associated with MTC clustering.Results: Although 3700 (41%) sequences belonged to MTCs, proportions differed substantially by country and subtype, ranging from 7% among UK subtype C sequences to 63% among German subtype B sequences. The probability of belonging to an MTC was independently less likely for women than men (OR = 0.66; P < 0.001), older individuals (OR = 0.79 per 10-year increase in age; P < 0.001) and people of non-white ethnicity (OR = 0.44; P < 0.001 and OR = 0.70; P = 0.002 for black and 'other' versus white, respectively). It was also more likely among men who have sex with men (MSM) than other risk groups (OR = 0.62; P < 0.001 and OR = 0.69; P = 0.002 for people who inject drugs, and sex between men and women, respectively), subtype B (ORs 0.36-0.70 for A, C, CRF01 and CRF02 versus B; all P < 0.05), having a well-estimated date of seroconversion (OR = 1.44; P < 0.001), a later calendar year of sampling (ORs 2.01-2.61 for all post-2002 periods versus pre-2002; all P < 0.01), and being naïve to antiretroviral therapy at sampling (OR = 1.19; P = 0.010).Conclusions: A high proportion (>40%) of individuals belonged to MTCs. Notably, the HIV epidemic dispersal appears to be driven by subtype B viruses spread within MSM networks. Expansion of regional epidemics seems mainly associated with recent MTCs, rather than the growth of older, established ones. This information is important for designing prevention and public health intervention strategies. [ABSTRACT FROM AUTHOR]