An investigation of trachoma vaccine regimens by the chlamydia vaccine CTH522 administered with cationic liposomes in healthy adults (CHLM-02): a phase 1, double-blind trial.

BACKGROUND: There is no vaccine against the major global pathogen Chlamydia trachomatis; its different serovars cause trachoma in the eye or chlamydia in the genital tract. We did a clinical trial administering CTH522, a recombinant version of the C trachomatis major outer membrane molecule, in different dose concentrations with and without adjuvant, to establish its safety and immunogenicity when administered intramuscularly, intradermally, and topically into the eye, in prime-boost regimens. METHODS: CHLM-02 was a phase 1, double-blind, randomised, placebo-controlled trial at the National Institute for Health Research Imperial Clinical Research Facility, London, UK. Participants were healthy men and non-pregnant women aged 18-45 years, without pre-existing C trachomatis genital infection. Participants were assigned into six groups by the electronic database in a pre-prepared randomisation list (A-F). Participants were randomly assigned (1:1:1:1:1) to each of the groups A-E (12 participants each) and 6 were randomly assigned to group F. Investigators were masked to treatment allocation. Groups A-E received investigational medicinal product and group F received placebo only. Two liposomal adjuvants were compared, CAF01 and CAF09b. The groups were intramuscular 85 µg CTH522-CAF01, or placebo on day 0 and two boosters or placebo at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (A); intramuscular 85 µg CTH522-CAF01, two boosters at day 28 and 112 with additional topical ocular administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (B); intramuscular 85 µg CTH522-CAF01, two boosters at day 28 and 112 with additional intradermal administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (C); intramuscular 15 µg CTH522-CAF01, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (D); intramuscular 85 µg CTH522-CAF09b, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (E); intramuscular placebo (F). The primary outcome was safety; the secondary outcome (humoral immunogenicity) was the percentage of trial participants achieving anti-CTH522 IgG seroconversion, defined as four-fold and ten-fold increase over baseline concentrations. Analyses were done as intention to treat and as per protocol. The trial is registered with ClinicalTrials.gov, NCT03926728, and is complete. FINDINGS: Between Feb 17, 2020 and Feb 22, 2022, of 154 participants screened, 65 were randomly assigned, and 60 completed the trial (34 [52%] of 65 women, 46 [71%] of 65 White, mean age 26·8 years). No serious adverse events occurred but one participant in group A2 discontinued dosing after having self-limiting adverse events after both placebo and investigational medicinal product doses. Study procedures were otherwise well tolerated; the majority of adverse events were mild to moderate, with only seven (1%) of 865 reported as grade 3 (severe). There was 100% four-fold seroconversion rate by day 42 in the active groups (A-E) and no seroconversion in the placebo group. Serum IgG anti-CTH522 titres were higher after 85 µg CTH522-CAF01 than 15 µg, although not significantly (intention-to-treat median IgG titre ratio groups A-C:D=5·6; p=0·062), with no difference after three injections of 85 µg CTH522-CAF01 compared with CTH522-CAF09b (group E). Intradermal CTH522 (group C) induced high titres of serum IgG anti-CTH522 neutralising antibodies against serovars B (trachoma) and D (urogenital). Topical ocular CTH522 (group B) at day 28 and 112 induced higher total ocular IgA compared with baseline (p<0·001). Participants in all active vaccine groups, particularly groups B and E, developed cell mediated immune responses against CTH522. INTERPRETATION: CTH522, adjuvanted with CAF01 or CAF09b, is safe and immunogenic, with 85 µg CTH522-CAF01 inducing robust serum IgG binding titres. Intradermal vaccination conferred systemic IgG neutralisation breadth, and topical ocular administration increased ocular IgA formation. These findings indicate CTH522 vaccine regimens against ocular trachoma and urogenital chlamydia for testing in phase 2, clinical trials. FUNDING: The EU Horizon Program TRACVAC.

Safety and immunogenicity of the H56:IC31 tuberculosis vaccine candidate in adults successfully treated for drug-susceptible pulmonary TB: a phase 1 randomized trial.

BACKGROUND: H56:IC31 is a candidate vaccine against tuberculosis (TB) with the potential to reduce TB recurrence rate. It is thus important for future clinical trials to demonstrate safety and immunogenicity of H56:IC31 in individuals treated for TB. METHODS: 22 adults confirmed to be Mtb negative (by 2 GeneXpert tests or 2 sputum cultures) after four-five months of TB treatment, and not more than 28 days after completion of TB treatment, were randomized to receive two doses of H56:IC31 (5 mg H56:500 nmol IC31; N=16) or placebo (N=6) 56 days apart. Participants were followed for 420 days for safety and immunogenicity. RESULTS: H56:IC31 vaccination was associated with an acceptable safety profile, consisting mostly of mild self-limited injection site reactions. No serious adverse events, and no vaccine-related severe adverse events, were reported. H56:IC31 induced a CD4+ T-cell response for Ag85B and ESAT-6, with ESAT-6 being immunodominant, which persisted through six months after the last vaccination. There was some evidence of CD8+ T-cell responses for both Ag85B and ESAT-6, but to a lesser extent than CD4+ responses. CONCLUSIONS: H56:IC31 was associated with an acceptable safety profile, and induced a predominant CD4+ T-cell response, in adults recently treated for drug-susceptible, uncomplicated pulmonary TB. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02375698.

Evaluation of Antimicrobial Properties, Cell Viability, and Metalloproteinase Activity of Bioceramic Endodontic Materials Used in Vital Pulp Therapy.

This study aimed to evaluate the antimicrobial properties, cell viability, and matrix metalloproteinase (MMP) inhibition capacity of several endodontic materials aimed at vital pulp therapy: Pro Root MTA®, EndoSequence®, Biodentine®, MTA Angelus®, TheraCal LC®, and BioC Repair®. The materials were prepared according to the manufacturer's instructions. Antimicrobial tests were conducted using a microcosm biofilm model, cell viability was assessed using murine fibroblasts (L929), and MMP activity was analyzed through electrophoresis. The results showed that BioC Repair®, Biodentine®, and EndoSequence® exhibited similar antimicrobial properties, while MTA Angelus® and ProRoot MTA® had inferior results but were comparable to each other. In terms of cell viability, no significant differences were observed among the materials. EndoSequence® demonstrated the highest MMP inhibition capacity. In conclusion, BioC Repair®, Biodentine®, EndoSequence®, and TheraCal® showed better antimicrobial properties among the tested materials. The materials did not exhibit significant differences in terms of cytotoxicity. However, EndoSequence® displayed superior MMP inhibition capacity.

Measures of Longitudinal Immune Dysfunction and Risk of AIDS and Non-AIDS Defining Malignancies in Antiretroviral-Treated People With Human Immunodeficiency Virus.

BACKGROUND: Human immunodeficiency virus (HIV) infection leads to chronic immune activation/inflammation that can persist in virally suppressed persons on fully active antiretroviral therapy (ART) and increase risk of malignancies. The prognostic role of low CD4:CD8 ratio and elevated CD8 cell counts on the risk of cancer remains unclear. METHODS: We investigated the association of CD4:CD8 ratio on the hazard of non-AIDS defining malignancy (NADM), AIDS-defining malignancy (ADM) and most frequent group of cancers in ART-treated people with HIV (PWH) with a CD4 and CD8 cell counts and viral load measurements at baseline. We developed Cox proportional hazard models with adjustment for known confounders of cancer risk and time-dependent cumulative and lagged exposures of CD4:CD8 ratio to account for time-evolving risk factors and avoid reverse causality. RESULTS: CD4:CD8 ratios below 0.5, compared to above 1.0, were independently associated with a 12-month time-lagged higher risk of ADM and infection-related malignancies (adjusted hazard ratio 2.61 [95% confidence interval {CI }1.10-6.19] and 2.03 [95% CI 1.24-3.33], respectively). CD4 cell counts below 350 cells/µL were associated with an increased risk of NADMs and ADMs, as did infection, smoking, and body mass index-related malignancies. CONCLUSIONS: In ART-treated PWH low CD4:CD8 ratios were associated with ADM and infection-related cancers independently from CD4 and CD8 cell counts and may alert clinicians for cancer screening and prevention of NADM.

Clonal hematopoiesis of indeterminate potential in persons with HIV.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with older age, inflammation and with risk of coronary artery disease (CAD). We aimed to characterize the burden of CHIP, and to explore the association between CHIP, inflammatory markers, and CAD in older persons with HIV (PWH). METHODS: From the Copenhagen Comorbidity in HIV Infection (COCOMO) study, we included 190 individuals older than 55 years of age. We defined CHIP as variant allele fraction at least 2%. CAD was categorized according to the most severe coronary artery lesion on coronary computed tomography (CT) angiography as no coronary atherosclerosis; any atherosclerosis defined as at least 1% stenosis and obstructive CAD defined as at least 50% stenosis. RESULTS: In the entire population (median age 66 years, 87% men), we identified a total of 62 mutations distributed among 49 (26%) participants. The three most mutated genes were DNMT3A , TET2 , and ASXL1 , accounting for 49, 25, and 16% of mutations, respectively. Age and sex were the only variables associated with CHIP. IL-1ß, IL-1Ra, IL-2, IL-6, IL-10, soluble CD14, soluble CD163 and TNF-α were not associated with CHIP, and CHIP was not associated with any atherosclerosis or with obstructive CAD in adjusted analyses. CONCLUSION: In older, well treated, Scandinavian PWH, more than one in four had at least one CHIP mutation. We did not find evidence of an association between CHIP and inflammatory markers or between CHIP and CAD. CHIP is an unlikely underlying mechanism to explain the association between inflammation and CAD in treated HIV disease.

Qualification of the differential leukocyte count and immunophenotyping in cryopreserved ex vivo whole blood assay.

We developed a flow cytometry-based assay, termed Differential Leukocyte Counting and Immunophenotyping in Cryopreserved Ex vivo whole blood (DLC-ICE), that allows quantification of absolute counts and frequencies of leukocyte subsets and measures expression of activation, phenotypic and functional markers. We evaluated the performance of the DLC-ICE assay by determining inter-operator variability for processing fresh whole blood (WB) from healthy donors collected at multiple clinical sites. In addition, we assessed inter-operator variability for staining of fixed cells and robustness across different anticoagulants. Accuracy was evaluated by comparing DLC-ICE measurements to real-time cell enumeration using an accredited hematology analyzer. Finally, we developed and tested the performance of a 27-colour immunophenotyping panel on cryopreserved fixed WB and compared results to matched fresh WB. Overall, we observed <20% variability in absolute counts and frequencies of granulocytes, monocytes and lymphocytes (T, B and NK cells) when fresh WB was collected in different anti-coagulant tubes, processed or stained by independent operators. Absolute cell counts measured across operators and anti-coagulants using the DLC-ICE method exhibited excellent correlation with the reference method, complete blood count (CBC) with differential, measured using a hematology analyzer (r2 > 0.9 for majority of measurements). A comparison of leukocyte immunophenotyping on fresh WB versus DLC-ICE processed blood yielded equivalent and linear results over a wide dynamic range (r2 = 0.94 over 10-104 cells/µL). These results demonstrate low variability across trained operators, high robustness, linearity and accuracy, supporting utility of the DLC-ICE assay for large cohort studies involving multiple clinical research sites.

Elevated Levels of Interleukin-1ß and Interleukin-10 Are Associated With Faster Lung Function Decline in People With Well-Treated Human Immunodeficiency Virus.

BACKGROUND: People with human immunodeficiency virus (PWH) have an increased risk of chronic lung diseases and chronic inflammation. We aimed to investigate if inflammatory markers and monocyte activation are associated with faster lung function decline in PWH. METHODS: We included 655 PWH from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study. Eligible participants were aged ≥25 years and had 2 spirometries separated by >2 years. Inflammatory markers (interleukin [IL]-1ß, IL-2, IL-6, IL-10, tumor necrosis factor-α, and interferon-γ) were measured at baseline by Luminex, and soluble CD14 and soluble CD163 by enzyme-linked immunosorbent assay. Using linear mixed models, we investigated whether elevated cytokine levels were associated with faster lung function decline. RESULTS: The majority of PWH were males (85.2%) with undetectable viral replication (95.3%). We found a faster decline in forced expiratory volume in 1 second (FEV1) in PWH with elevated IL-1ß and IL-10, with an additional decline of 10.3 mL/year (95% confidence interval [CI], 2.1-18.6; P = .014) and 10.0 mL/year (95% CI, 1.8-18.2; P = .017), respectively. We found no interaction between smoking and IL-1ß or IL-10 on FEV1 decline. CONCLUSIONS: Elevated IL-1ß and IL-10 were independently associated with faster lung function decline in PWH, suggesting that dysregulated systemic inflammation may play a role in the pathogenesis of chronic lung diseases.

Association between ten-eleven methylcytosine dioxygenase 2 genetic variation and viral load in people with HIV.

INTRODUCTION: Identifying genetic factors that influence HIV-pathogenesis is critical for understanding disease pathways. Previous studies have suggested a role for the human gene ten-eleven methylcytosine dioxygenase 2 (TET2) in modulating HIV-pathogenesis. METHODS: We assessed whether genetic variation in TET2 was associated with markers of HIV-pathogenesis using both gene level and single nucleotide polymorphism (SNP) level association in 8512 HIV-positive persons across five clinical trial cohorts. RESULTS: Variation at both the gene and SNP-level of TET2 was found to be associated with levels of HIV viral load (HIV-VL) consistently in the two cohorts that recruited antiretroviral-naïve participants. The SNPs occurred in two clusters of high linkage disequilibrium (LD), one associated with high HIV-VL and the other low HIV-VL, and were predominantly found in Black participants. CONCLUSION: Genetic variation in TET2 was associated with HIV-VL in two large antiretroviral therapy (ART)-naive clinical trial cohorts. The role of TET2 in HIV-pathogenesis warrants further investigation.

Investigation of Causal Effects of Protein Biomarkers on Cardiovascular Disease in Persons With HIV.

BACKGROUND: There is an incompletely understood increased risk for cardiovascular disease (CVD) among people with HIV (PWH). We investigated if a collection of biomarkers were associated with CVD among PWH. Mendelian randomization (MR) was used to identify potentially causal associations. METHODS: Data from follow-up in 4 large trials among PWH were used to identify 131 incident CVD cases and they were matched to 259 participants without incident CVD (controls). Tests of associations between 460 baseline protein levels and case status were conducted. RESULTS: Univariate analysis found CLEC6A, HGF, IL-6, IL-10RB, and IGFBP7 as being associated with case status and a multivariate model identified 3 of these: CLEC6A (odds ratio [OR] = 1.48, P = .037), HGF (OR = 1.83, P = .012), and IL-6 (OR = 1.45, P = .016). MR methods identified 5 significantly associated proteins: AXL, CHI3L1, GAS6, IL-6RA, and SCGB3A2. CONCLUSIONS: These results implicate inflammatory and fibrotic processes as contributing to CVD. While some of these biomarkers are well established in the general population and in PWH (IL-6 and its receptor), some are novel to PWH (HGF, AXL, and GAS6) and some are novel overall (CLEC6A). Further investigation into the uniqueness of these biomarkers in PWH and the role of these biomarkers as targets among PWH is warranted.

BKPyV DNAemia in Kidney Transplant Recipients Undergoing Regular Screening: A Single-Centre Cohort Study.

Infection with BK polyomavirus (BKPyV) is a common opportunistic infection after kidney transplantation (KT) and may affect graft function. We aimed to determine the incidence, risk factors, and clinical outcomes of BKPyV DNAemia in a prospective cohort of 601 KT recipients transplanted from 2012 to 2020. BKPyV PCR on plasma was performed at days 60, 90, 180, 270, and 360 post-KT. Any BKPyV DNAemia was defined as a single BKPyV DNA of ≥1000 copies/mL. Severe BKPyV DNAemia was defined as two consecutive BKPyV DNA of ≥10,000 copies/mL. Cumulative incidences were investigated using the Aalen-Johansen estimator, and the risk factors were investigated in Cox proportional hazard models. The incidence of any BKPyV DNAemia and severe BKPyV DNAemia was 21% (18-25) and 13% (10-16) at one year post-KT, respectively. Recipient age > 50 years (aHR, 1.72; 95% CI 1.00-2.94; p = 0.049), male sex (aHR, 1.96; 95% CI 1.17-3.29; p = 0.011), living donors (aHR, 1.65; 95% CI 1.03-2.74; p = 0.045), and >3 HLA-ABDR mismatches (aHR, 1.72; 95% CI 1.01-2.94; p = 0.046) increased the risk of severe BKPyV DNAemia. Any BKPyV DNAemia was associated with an increased risk of graft function decline (aHR, 2.26; 95% CI 1.00-5.12; p = 0.049), and severe BKPyV DNAemia was associated with an increased risk of graft loss (aHR, 3.18; 95% CI 1.06-9.58; p = 0.039). These findings highlight the importance of BKPyV monitoring post-KT.

Chlamydia trachomatis vaccine development - a view on the current challenges and how to move forward.

INTRODUCTION: Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen in the world. A licensed vaccine is not yet available, but the first vaccines have entered clinical trials. AREAS COVERED: We describe the progress that has been made in our understanding of the type of immunity that a protective vaccine should induce, and the challenges that vaccine developers face. We also focus on the clinical development of a chlamydia vaccine. The first chlamydia vaccine candidate has now been tested in a clinical phase I trial, and another phase I trial is currently running. We discuss what it will take to continue this development and what future trial setups could look like. EXPERT OPINION: The chlamydia field is coming of age and the first phase I clinical trial of a C. trachomatis vaccine has been successfully completed. We expect and hope that this will motivate various stakeholders to support further development of chlamydia vaccines in humans.

Cytomegalovirus viremia and risk of disease progression and death in HIV-positive patients starting antiretroviral therapy.

OBJECTIVE: The aim of this study was to assess the prevalence of cytomegalovirus (CMV) viremia in HIV-positive patients starting antiretroviral therapy (ART) and to evaluate its impact on clinical outcomes. DESIGN: A retrospective analysis of four clinical trials (INSIGHT FIRST, SMART, START, and ANRS REFLATE TB). METHODS: Stored plasma samples from participants were used to measure CMV viremia at baseline prior to initiating ART and at visits through 1 year of follow-up after ART initiation. CMV viremia was measured centrally using a quantitative PCR assay. Within FIRST, associations of CMV viremia at baseline and through 8 months of ART were examined with a composite clinical outcome of AIDS, serious non-AIDS events, or death using Cox proportional hazards regression. RESULTS: Samples from a total of 3176 participants, 1169 from FIRST, 137 from ANRS REFLATE TB, 54 from SMART, and 1816 from START were available with baseline CMV viremia prevalence of 17, 26, 0, and 1%, respectively. Pooled across trials, baseline CMV viremia was associated with low CD4 + T-cell counts and high HIV RNA levels. In FIRST, CMV viremia was detected in only 5% of participants between baseline and month 8. After adjustment for CD4 + T-cell count and HIV RNA levels, hazard ratios for risk of clinical outcomes was 1.15 (0.86-1.54) and 2.58 (1.68-3.98) in FIRST participants with baseline and follow-up CMV viremia, respectively. CONCLUSION: Baseline CMV viremia in HIV-positive patients starting ART is associated with advanced infection and only persistent CMV viremia after ART initiation is associated with a higher risk of morbidity and mortality.

Cartografia dos serviços de acolhimento ao acadêmico em sofrimento psíquico nas universidades públicas brasileiras / Cartography of the welcoming services for students with psychological distress in brazilian public universities / Cartografía de los servicios de recepción a estudiantes con padecimientos psicológicos en universidades públicas de brasil

RESUMO Objetivo: mapear os serviços de acolhimento em saúde mental ofertados aos acadêmicos pelas universidades públicas brasileiras. Método: pesquisa documental apresentada como cartografia das universidades públicas presenciais brasileiras. Os dados foram coletados de agosto a outubro de 2019 no site do Ministério da Educação, segundo as variáveis: informações sobre o serviço de acolhimento, modalidade de acesso, atividades ofertadas, distribuição geográfica das universidades que ofertam o serviço no Brasil. Resultados: das 107 universidades, 73 referem ter um serviço de acolhimento em saúde mental, e destas, 43 informam a modalidade de acesso, sendo a maioria o agendamento, e os tipos de atividades desenvolvidas, com respeito ao Plantão Psicológico. Considerações Finais: com o aumento de sofrimento psíquico entre acadêmicos, é missão da academia dialogar e acolher essa demanda. O estudo contribui alertando para a necessidade da expansão desses serviços.

ABSTRACT Objective: to map the welcoming services in Mental Health offered to students by Brazilian public universities. Method: a documentary research study presented as a cartography of the Brazilian public universities that offer in-person courses. The data were collected from August to October 2019 on the Ministry of Education website, according to the following variables: information about the welcoming service, access modality, activities offered; and geographic distribution of the universities offering the service in Brazil. Results: of the 107 universities, 73 report having a welcoming service in Mental Health and, of these, 43 indicate the access modality, mostly through appointment scheduling, and the types of activities developed with respect to Psychological Emergency Care. Final Considerations: with the increase in psychological distress among students, it is the university's duty to be an interlocutor and welcome this demand. The study contributes by warning about the need to expand these services.

RESUMEN Objetivo: mapear los servicios de recepción en Salud Mental que ofrecen las universidades públicas de Brasil a sus estudiantes. Método: investigación documental presentada en la forma de una cartografía de las universidades públicas con carreras presenciales de Brasil. Los datos se recolectaron entre agosto y octubre de 2019 en el sitio web del Ministerio de Educación, de acuerdo con las siguientes variables: información sobre el servicio de recepción, modalidad de acceso, actividades ofrecidas y distribución geográfica de las universidades que ofrecen el servicio en Brasil. Resultados: de las 107 universidades, 73 informan tener un servicio de recepción en salud mental y, de estas, 43 indican la modalidad de acceso, la mayoría por medio de cita previa, y los tipos de actividades que se desarrollan, con respecto a la Psicología de emergencia. Consideraciones Finales: dado el incremento en los índices de padecimiento psicológico entre los estudiantes, la misión de las universidades es ser interlocutores y receptores de dicha demanda. El aporte del estudio es advertir acerca de la necesidad de expandir estos servicios.

Independent Associations of Tumor Necrosis Factor-Alpha and Interleukin-1 Beta With Radiographic Emphysema in People Living With HIV.

Background: People living with HIV (PLWH) have increased systemic inflammation, and inflammation has been suggested to contribute to the pathogenesis of emphysema. We investigated whether elevated cytokine concentrations (interleukin (IL)-1ß, IL-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-6, IL-10, IL-17A, tumor necrosis factor-alpha (TNFα), interferon-gamma (IFNγ), soluble CD14 (sCD14) and sCD163 were independently associated with radiographic emphysema in PLWH. Methods: We included PLWH from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study without hepatitis B and C co-infection and with a plasma sample and a chest computed tomography scan available. Emphysema plus trace emphysema was defined as the percentage of low attenuation area under -950 Houndsfield Unit (%LAA-950) using a cut-off at 5%. Cytokine concentrations were measured by ELISA or Luminex immunoassays. An elevated cytokine concentration was defined as above the 75th percentile. Results: Of 783 PLWH, 147 (18.8%) had emphysema. PLWH were predominantly male (86.0%) and 743 (94.9%) had undetectable viral replication. PLWH with emphysema had higher concentrations of TNFα (median (IQR): 8.2 (6.4-9.8) versus 7.1 (5.7-8.6) pg/ml, p<0.001), IL-1ß (0.21 (0.1-0.4) versus 0.17 (0.1-0.3) pg/ml, p=0.004) and IL-6 (3.6 (2.6-4.9) versus 3.1 (2.0-4.3) pg/ml, p=0.023) than PLWH without. In a logistic regression model adjusted for age, sex, ethnicity, smoking status, BMI and CD4 nadir, elevated TNFα (adjusted odds ratio (aOR): 1.78 [95%CI: 1.14-2.76], p=0.011) and IL-1ß (aOR: 1.81 [95%CI: 1.16-2.81], p=0.009) were independently associated with emphysema. The association between IL-1ß and emphysema was modified by smoking (p-interaction=0.020) with a more pronounced association in never-smokers (aOR: 4.53 [95%CI: 2.05-9.98], p<0.001). Conclusion: Two markers of systemic inflammation, TNFα and IL-1ß, were independently associated with emphysema in PLWH and may contribute to the pathogenesis of emphysema. Importantly, the effect of IL-1ß seems to be mediated through pathways that are independent of excessive smoking. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02382822.

Prevalence and Outcomes for Heavily Treatment-Experienced Individuals Living With Human Immunodeficiency Virus in a European Cohort.

BACKGROUND: Although antiretroviral treatments have improved survival of persons living with HIV, their long-term use may limit available drug options. We estimated the prevalence of heavily treatment-experienced (HTE) status and the potential clinical consequences of becoming HTE. SETTING: EuroSIDA, a European multicenter prospective cohort study. METHODS: A composite definition for HTE was developed, based on estimates of antiretroviral resistance and prior exposure to specific antiretroviral regimens. Risks of progressing to clinical outcomes were assessed by Poisson regression, comparing every HTE individual with 3 randomly selected controls who never became HTE. RESULTS: Of 15,570 individuals under follow-up in 2010-2016, 1617 (10.4%, 95% CI: 9.9% to 10.9%) were classified as HTE. 1093 individuals became HTE during prospective follow-up (HTE incidence rate 1.76, CI: 1.66 to 1.87 per 100 person-years of follow-up). The number of HTE individuals was highest in West/Central Europe (636/4019 persons, 15.7%) and lowest in East Europe (26/2279 persons, 1.1%). Although most HTE individuals maintained controlled viral loads (<400 copies/mL), many had low CD4 counts (≤350 cells/µL). After controlling for age, immunological parameters and pre-existing comorbidities, HTE status was not associated with the risk of new AIDS (adjusted incidence rate ratio, aIRR 1.44, CI: 0.86 to 2.40, P = 0.16) or non-AIDS clinical events (aIRR 0.96, CI: 0.74 to 1.25, P = 0.77). CONCLUSIONS: HTE prevalence increased with time. After adjusting for key confounding factors, there was no evidence for an increased risk of new AIDS or non-AIDS clinical events in HTE. Additional therapeutic options and effective management of comorbidities remain important to reduce clinical complications in HTE individuals.

Physicomechanical Properties of Tertiary Monoblock in Endodontics: A Systematic Review and Meta-analysis.

Introduction: A systematic review and meta-analysis were conducted to evaluate the physicomechanical properties of tertiary monoblock obturation with different obturation techniques. Methods and Materials: PubMed (MEDLINE), Web of Science, Scopus, the Cochrane Library, LILACS, IBECS, and BBO were searched time. PICO question was: "In extracted human teeth (Population), does tertiary monoblock obturation (Intervention) have superior physicomechanical properties (Outcome) compared to conventional obturation systems (Comparison)?". Statistical analyses for push-out bond strength were performed with RevMan software by comparing the mean differences of each study, with a 95% confidence interval. Inverse variance was used as statistical method, random-effects models as analysis model, and heterogeneity between studies was assessed by Cochran's Q test and I2 statistic (P <0.05). Results: Of 2162 studies retrieved, 31 were included in this review for "Study Characteristics". Ten studies were included in the meta-analysis. Analysis demonstrated that conventional obturation had significantly higher push-out bond strength than tertiary monoblock obturation (P <0 .01), with a mean difference of -1.00 (95% CI, -1.41 to -0.58; I2=100%). Subgroups using single-cone and cold lateral condensation techniques showed significantly lower push-out bond strength for tertiary monoblock obturation (P <0.01), respectively with a mean difference of -0.09 (95% CI, -1.13 to -0.67; I2=97%) and of -1.97 (95% CI, -3.19 to -0.75; I2=100%). The warm vertical compaction subgroup showed no statistically significant difference between tertiary monoblock and conventional systems (P =0.13), with a mean difference of 0.49 (95% CI, -0.14 to 1.12; I2=10%). Conclusion: Tertiary monoblock systems have a push-out bond strength similar to conventional systems when used with warm vertical compaction.

Effects of Brown and Green Propolis on Bond Strength of Fiberglass Posts to Root Canal Dentin.

Introduction: The purpose of this study was to evaluate the effect of brown and green propolis on bond strength of the fiberglass posts to root canal dentin, and to compare it with conventional endodontic irrigants. Methods and Materials: Sixty bovine teeth were selected, decoronated and randomly distributed into six groups (n=10), according to the irrigation solution: 0.9% saline solution (Control); 2% chlorhexidine (CHX); 5% malic acid (MA); 0.5% ethanolic extract of brown propolis (BP); 0.25% ethanolic extract of green propolis (GP); 2.5% sodium hypochlorite (NaOCl). After root canal treatment, fiber posts were cemented into prepared root canals with a self-adhesive resin cement. The roots were cross-sectioned to obtain two discs from each third and submitted to the micro push-out test. Failure patterns were evaluated under optical microscopy. The influence of irrigants agents was analyzed using one-way ANOVA followed by Games-Howell's test (α=0.05). Failure modes were analyzed using Fischer's exact test (α=0.05). Results: There were statistically significant differences among the groups (P<0.05). The control, NaOCl and BP groups showed the highest bond strength with no statistically significant difference between them (P>0.05). Adhesive failure type was the predominant in all groups. Conclusion: Based on this in vitro study, the use of 0.5% brown propolis did not influence the bond strength of fiberglass posts to root canal dentin, while the use of 0.25% green propolis did affect it negatively.

Independent Association of Interleukin 6 With Low Dynamic Lung Function and Airflow Limitation in Well-Treated People With Human Immunodeficiency Virus.

BACKGROUND: Human immunodeficiency virus (HIV) infection is associated with an increased risk of chronic pulmonary diseases. We compared cytokine concentrations (interleukin 6 [IL-6], interleukin 1ß, 2, 4, 10, and 17A, tumor necrosis factor α, interferon γ, soluble CD14 [sCD14] and soluble CD163 [sCD163]) in people with HIV (PWH) and uninfected controls and investigated whether elevated cytokine concentrations were independently associated with lung function indices in PWH. METHODS: We performed spirometry and measured cytokine concentrations by Luminex immunoassays or enzyme-linked immunoassay in 951 PWH and 79 uninfected controls from the Copenhagen Comorbidity in HIV Infection study. Regression analyses were used to explore associations between elevated cytokine concentrations and lung function indices. RESULTS: PWH were predominantly male (84.6%) and 94.2% had undetectable viral replication. In PWH, elevated IL-6 was associated with lower forced expiratory volume in 1 second (-212 mL [95% confidence interval, -308 to -116 mL]), lower forced vital capacity (-208 mL [-322 to -93 mL]), and airflow limitation (aOR, 2.62 [1.58-4.36]) (all P < .001) in models adjusted for age, sex, ethnicity, smoking status, body mass index, and CD4 T-cell nadir. The association between IL-6 and dynamic lung function was modified by smoking (P for interaction = .005). CONCLUSION: IL-6 levels were elevated and independently associated with low dynamic lung function and airflow limitation in well-treated PWH, suggesting that systemic inflammation may contribute to the pathogenesis of chronic pulmonary diseases.

Effect of post space preparation drills on the incidence of root dentin defects.

OBJECTIVES: This study investigated the incidence of root dentin defects after the use of different post space preparation (PSP) drills. MATERIALS AND METHODS: Seventy-two bovine incisors were selected and obtained 14-mm-long root sections. Twelve roots served as controls with no intervention (G1). The 60 root canals remaining were instrumented using the crown-down technique with the ProTaper Next system and obturated using the lateral condensation technique. Specimens were randomly distributed into 5 groups (n = 12) according to the operative steps performed: G2, root canal instrumentation and filling (I+F); G3, I+F and PSP with Gates-Glidden drills; G4, I+F and PSP with Largo-Peeso reamers; G5, I+F and PSP with Exacto drill; and G6, I+F and PSP with WhitePost drill. Roots were sectioned at 3, 6, 9, and 12 mm from the apex, and digital images were captured. The presence of root dentin defects was recorded. Data were analyzed by the χ2 test, with p < 0.05 considered to indicate statistical significance. RESULTS: Root dentin defects were observed in 39.6% of the root sections. No defects were observed in G1. G5 had significantly more cracks and craze lines than G1, G2, and G3 (p < 0.05), and more fractures than G1, G2, G3, and G4 (p < 0.05). When all root sections were analyzed together, significantly more defects were observed at the 12-mm level than at the 3-mm level (p < 0.05). CONCLUSIONS: PSP drills caused defects in the root dentin. Gates-Glidden drills caused fewer root defects than Largo-Peeso reamers and Exacto drills.