Baseline biomarkers of efficacy and on-treatment immune-profile changes associated with bempegaldesleukin plus nivolumab.

In PIVOT IO 001 (NCT03635983), the combination of the investigational interleukin-2 agonist bempegaldesleukin (BEMPEG) with nivolumab (NIVO) had no added clinical benefit over NIVO monotherapy in unresectable/metastatic melanoma. Pre-defined baseline and on-treatment changes in selected biomarkers were analyzed to explore the potential mechanisms underlying the clinical observations. In each treatment arm, higher baseline tumor mutational burden or immune infiltration/inflammation was associated with improved efficacy compared with lower levels.

Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results.

Purpose: Despite marked advances in the treatment of unresectable or metastatic melanoma, the need for novel therapies remains. Bempegaldesleukin (BEMPEG), a pegylated interleukin-2 (IL-2) cytokine prodrug, demonstrated efficacy in the phase II PIVOT-02 trial. PIVOT IO 001 (ClinicalTrials.

A Common NLRC4 Gene Variant Associates With Inflammation and Pulmonary Function in Human Immunodeficiency Virus and Tuberculosis.

Background: Inflammasomes mediate inflammation in adults living with both human immunodeficiency virus (HIV) and tuberculosis (TB), but the relevance of inflammasome gene polymorphisms in TB-associated pulmonary damage is unknown. We hypothesized that functional single-nucleotide polymorphisms (SNPs) in inflammasome pathway genes modify systemic and pulmonary inflammation, contributing to respiratory impairment in adults living with HIV/pulmonary TB.

Methods: This was a prospective cohort study set in South Africa following individuals living with HIV/TB up to 48 weeks post-antiretroviral therapy (ART) initiation.

Declines in Lung Function After Antiretroviral Therapy Initiation in Adults With Human Immunodeficiency Virus and Tuberculosis: A Potential Manifestation of Respiratory Immune Reconstitution Inflammatory Syndrome.

End-organ impairment has received relatively little research attention as a possible manifestation of tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS). In this prospective cohort study, one-half of adults with human immunodeficiency virus and pulmonary tuberculosis experienced meaningful declines in lung function on antiretroviral therapy, suggesting a role for lung function in TB-IRIS definitions.

Optimizing ethambutol dosing among HIV/tuberculosis co-infected patients: a population pharmacokinetic modelling and simulation study.

Background: Reduced ethambutol serum concentrations are commonly observed among TB patients co-infected with HIV and may lead to treatment failure.

Objectives: To perform a population pharmacokinetic study of ethambutol in HIV/TB patients, and to evaluate an intensified ethambutol weight-based dosing strategy to support pharmacokinetic target attainment.

Methods: We conducted a prospective study of ethambutol pharmacokinetics among HIV/TB patients administered first-line TB treatment in Botswana, with study visits before and after initiation of ART.

Lung Injury on Antiretroviral Therapy in Adults With Human Immunodeficiency Virus/Tuberculosis.

Background: Immune restoration on antiretroviral therapy (ART) can drive inflammation in people living with human immunodeficiency virus (HIV) who have pulmonary tuberculosis (TB), but its effects on the lungs have not been assessed. We evaluated associations between pulmonary inflammation, recovery of pathogen-specific CD4 T-cell function, and lung injury prior to and after ART initiation in adults with HIV and pulmonary TB.

Methods: This was a prospective cohort study in South Africa, following adults with HIV and pulmonary TB prior to and up to 48 weeks after ART initiation.

Common Variation in Is Associated With Early Death and Elevated Inflammasome Biomarkers Among Advanced HIV/TB Co-infected Patients in Botswana.

Background: Elevated inflammation is associated with early mortality among HIV/tuberculosis (TB) patients starting antiretroviral therapy (ART); however, the sources of immune activation are unclear. We hypothesized that common variation in innate immune genes contributes to excessive inflammation linked to death. As single nucleotide polymorphisms (SNPs) in inflammasome pathway genes can increase risk for inflammatory diseases, we investigated their association with early mortality among a previously described cohort of HIV/TB patients initiating ART in Botswana.

Tuberculosis and lung damage: from epidemiology to pathophysiology.

A past history of pulmonary tuberculosis (TB) is a risk factor for long-term respiratory impairment. Post-TB lung dysfunction often goes unrecognised, despite its relatively high prevalence and its association with reduced quality of life. Importantly, specific host and pathogen factors causing lung impairment remain unclear.

Pyrazinamide clearance is impaired among HIV/tuberculosis patients with high levels of systemic immune activation.

Pyrazinamide is the main driver of sterilizing effect in the standard regimen in adults and older children, and this effect is concentration-dependent. Tuberculosis patients co-infected with human immunodeficiency virus (HIV) have an increased risk for poor tuberculosis treatment outcomes and adverse drug events. We sought to determine whether measures of systemic immune activation were related to pyrazinamide pharmacokinetics among HIV/tuberculosis patients.

Markers of gut dysfunction do not explain low rifampicin bioavailability in HIV-associated TB.

Background: Rifampicin is the key drug responsible for sterilizing activities in the first-line TB treatment regimen. Damage to the gut during acute and chronic HIV infection may inhibit drug absorptive capacity. We sought to test the hypothesis that markers of intestinal damage, bacterial translocation and systemic immune activation would relate to rifampicin bioavailability among HIV/TB patients.

Elevated Pre-Antiretroviral Therapy CD39+CD8+ T Cell Frequency Is Associated With Early Mortality in Advanced Human Immunodeficiency Virus/Tuberculosis Co-infection.

Correlates of death soon after antiretroviral therapy (ART) initiation remain unclear. We investigated the association between expression of CD39, a novel immune exhaustion marker, and early mortality in patients with human immunodeficiency virus/tuberculosis co-infection. Elevated pre-ART CD39+CD8+ T cell frequency was independently associated with mortality within 6 months of ART initiation.

Isoniazid clearance is impaired among human immunodeficiency virus/tuberculosis patients with high levels of immune activation.

Aims: Immune activation, which is characteristic of both tuberculosis (TB) and human immunodeficiency virus (HIV) infection, is associated with impaired drug metabolism. We tested the hypothesis that elevated levels of systemic immune activation among adults with HIV/TB initiating antiretroviral therapy (ART) would be associated with impaired clearance of isoniazid.

Methods: We conducted a prospective observational study of isoniazid pharmacokinetics (PK) and systemic immune activation prior to and 1 month after ART initiation.

Matrix Metalloproteinases in Tuberculosis-Immune Reconstitution Inflammatory Syndrome and Impaired Lung Function Among Advanced HIV/TB Co-infected Patients Initiating Antiretroviral Therapy.

Background: HIV-infected patients with pulmonary TB (pTB) can have worsening of respiratory symptoms as part of TB-immune reconstitution inflammatory syndrome (TB-IRIS) following antiretroviral therapy (ART) initiation. Thus, reconstitution of immune function on ART could drive incident lung damage in HIV/TB.

Methods: We hypothesized that increases in matrix metalloproteinases (MMPs), which can degrade lung matrix, on ART are associated with TB-IRIS among a cohort of advanced, ART naïve, HIV-infected adults with pTB.

Robust Reconstitution of Tuberculosis-Specific Polyfunctional CD4+ T-Cell Responses and Rising Systemic Interleukin 6 in Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome.

Background: The immunopathogenesis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains unclear. We determined the association between pathogen-specific T-cell responses and development of paradoxical TB-IRIS on antiretroviral therapy (ART).

Methods: This study was nested within a prospective cohort study of HIV-infected patients with active pulmonary tuberculosis and baseline CD4 counts ≤125 cells/µL initiating ART.

Immunological profiling of tuberculosis-associated immune reconstitution inflammatory syndrome and non-immune reconstitution inflammatory syndrome death in HIV-infected adults with pulmonary tuberculosis starting antiretroviral therapy: a prospective observational cohort study.

Background: Patients co-infected with advanced HIV and tuberculosis are at risk of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) and death soon after initiation of antiretroviral therapy (ART). Tuberculosis-associated IRIS has been associated with quicker recovery of cellular immune responses after ART initiation and early mortality with slower recovery of these responses. We aimed to assess whether patients who have these outcomes have distinct immunological profiles before and after ART initiation.

Outcomes in HIV-infected adults with tuberculosis at clinics with and without co-located HIV clinics in Botswana.

Setting: Gaborone, Botswana.

Objective: To determine if starting anti-tuberculosis treatment at clinics in Gaborone without co-located human immunodeficiency virus (HIV) clinics would delay time to highly active antiretroviral therapy (HAART) initiation and be associated with lower survival compared to starting anti-tuberculosis treatment at clinics with on-site HIV clinics.

Design: Retrospective cohort study.

Early immunologic failure is associated with early mortality among advanced HIV-infected adults initiating antiretroviral therapy with active tuberculosis.

Background: The relationship between antiretroviral therapy (ART) response and early mortality after ART initiation is unknown. We hypothesized that early mortality is associated with decreased early immunologic response to ART.

Methods: We prospectively determined the association between changes in plasma human immunodeficiency virus type 1 (HIV-1) RNA and CD4(+) T-cell counts (CD4 count) after 4 weeks of ART and early mortality in adults with pulmonary tuberculosis and pre-ART CD4 counts ≤ 125 cells/µL.

Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity.

CCAAT/enhancer binding protein (C/EBP)β, and C/EBP binding sites in the HIV/SIV-long terminal repeat (LTR) are crucial for regulating transcription and for IFNβ-mediated suppression of virus replication in macrophages, the predominant source of productive virus replication in the brain. We investigated sequence variation within the SIV-LTR C/EBP sites that may be under selective pressure in vivo and therefore associated with disease progression. Using the SIV-macaque model, we examined viral LTR sequences derived from the spleen, a site of macrophage and lymphocyte infection, and the brain from macaques euthanized at 10, 21, 42, 48 and 84 days postinoculation (p.

Regulation of SIV mac 239 basal long terminal repeat activity and viral replication in macrophages: functional roles of two CCAAT/enhancer-binding protein beta sites in activation and interferon beta-mediated suppression.

CCAAT/enhancer-binding protein (C/EBP) beta and C/EBP sites in the HIV-1 long terminal repeat (LTR) are crucial for HIV-1 replication in monocyte/macrophages and for the ability of interferon beta (IFN beta) to inhibit ongoing active HIV replication in these cells. This IFN beta-mediated down-regulation involves induction of the truncated, dominant-negative isoform of C/EBP beta referred to as liver-enriched transcriptional inhibitory protein (LIP). Although binding of the C/EBP beta isoform to C/EBP sites in the simian immunodeficiency virus (SIV) LTR has previously been examined, the importance of these sites in core promoter-mediated transcription, virus replication, IFN beta-mediated regulation, and the relative binding of the two isoforms (C/EBP beta and LIP) has not been investigated.

Rare case of renal cell carcinoma with double inferior vena cava with venous thrombosis.

Double inferior vena cava is a rare congenital anomaly. Recognition of such venous anomalies is important in the evaluation and surgical treatment of retroperitoneal disease. Newer radiological modalities such as three-dimensional reconstruction of spiral computed tomography help to define such anomalies and avoid significant morbidity during surgical exploration.

Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse.

Retroviruses, acting as somatic cell insertional mutagens, have been widely used to identify cancer genes in the haematopoietic system and mammary gland. An insertional mutagen for use in other mouse somatic cells would facilitate the identification of genes involved in tumour formation in a wider variety of tissues. Here we report the ability of the Sleeping Beauty transposon to act as a somatic insertional mutagen to identify genes involved in solid tumour formation.

Postoperative pulmonary function in laparoscopic versus open cholecystectomy: prospective, comparative study.

Background: Pulmonary complications remain a leading cause of morbidity after major abdominal operations.

Objective: To compare pulmonary function and the frequency of pulmonary complications after laparoscopic cholecystectomy (LC) and open cholecystectomy (OC).

Methods: Fifty-five patients with symptomatic gallstone disease undergoing elective cholecystectomy (LC 40, OC 15) under general anesthesia were evaluated using pulmonary function tests (forced vital capacity [FVC], forced expiratory volume at 1 second [FEV1], and forced expiratory flow at 25% to 75% [FEF25% -75%], chest X-ray and pulse oximetry before and after surgery.