Vaporized nicotine use among patients in HIV care who smoke tobacco: perceived health effects and effectiveness as a smoking cessation tool.

Evidence suggests adverse health effects from vaporized nicotine (VN) use, such as electronic "e" cigarettes, and limited efficacy to aid tobacco cessation. People with HIV (PWH) smoke tobacco at higher rates than the general population, with greater morbidity, highlighting the necessity of effective tobacco cessation tools. PWH may be more vulnerable to adverse effects of VN. Using semi-structured 1:1 interviews, we examined health beliefs regarding VN, patterns of use, and perceived effectiveness for tobacco cessation among PWH in HIV care at three geographically diverse U.S. sites. PWH (n = 24) had limited understanding of VN product content or health effects, presuming VN less harmful than tobacco cigarettes (TC). VN failed to adequately replicate the psychoactive effects or desired ritual of smoking TC. Concurrent TC use, and continuous VN use throughout the day, was common. Satiety using VN was elusive, and consumption quantity was difficult to track. VN had limited desirability and durability as a TC cessation tool among the interviewed PWH.

AtbFinder Diagnostic Test System Improves Optimal Selection of Antibiotic Therapy in Persons with Cystic Fibrosis.

Cystic fibrosis (CF) is characterized by mutations of CFTR that lead to increased viscous secretions, bacterial colonization, and recurrent infections. Chronic Pseudomonas aeruginosa infection in persons with CF is associated with progressive and accelerated lung function decline despite aggressive antibiotic treatment. We report the management of respiratory infections in persons with CF with antibiotic therapy that was based on the recommendations of AtbFinder, a novel, rapid, culture-based diagnostic test system that employs a novel paradigm of antibiotic selection. AtbFinder mimics bacterial interactions with antibiotics at concentrations that can be achieved in affected tissues or organs and models conditions of interbacterial interactions within polymicrobial biofilms. This open-label, single-arm, investigator-initiated clinical study was designed to identify the efficacy of antibiotics selected using AtbFinder in persons with CF. Microbiological and clinical parameters were assessed following the change of antibiotic therapy to antibiotics selected with AtbFinder between January 2016 and December 2018 and retrospectively compared with clinical data collected between January 2013 and December 2015. We enrolled 35 persons with CF (33 with chronic P. aeruginosa colonization). Antibiotics selected using AtbFinder resulted in clearance of P. aeruginosa in 81.8% of subsequent cultures, decreased pulmonary exacerbations from 1.21 per patient per annum to 0, and an increase in predicted percent predicted forced expiratory volume in 1 s up to 28.4% from baseline. The number of systemic antibiotic courses used in patients after switching to the AtbFinder-selected therapy was reduced from 355 to 178. These findings describe the superiority of antibiotic regimens selected with AtbFinder compared with routine antimicrobial susceptibility testing.

Epstein-Barr virus infection after adolescence and human herpesvirus 6A as risk factors for multiple sclerosis.

BACKGROUND AND PURPOSE: Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. METHODS: In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). CONCLUSIONS: This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS.

Prevalencia de Neisseria gonorrhoeae, en reclusos del Centro de Detención Preventiva de Arica / Prevalence of Neisseria gonorrhoeae, amongst inmates of the Preventive Reclusion Center in Arica

Resumen Introducción: Los/as trabajadores/as sexuales, personas con adicción a drogas, población de inicio sexual precoz y población penal son considerados los grupos de mayor riesgo de contraer infecciones de transmisión sexual (ITS). Objetivo: Determinar prevalencia de infección por Neisseria gonorrhoeae, en reclusos del Centro de Detención Preventiva (CDP) de la Región de Arica y Parinacota, Chile. Este estudio contó con la aprobación del Cómité Ético Científico de la Universidad de Tarapacá. Material y Método: Participaron 140 reclusos, que aceptaron ser parte del estudio en forma voluntaria y firmaron un consentimiento informado. Se tomó una muestra del meato uretral para pesquisa de N. gonorrhoeae y se aplicó una encuesta epidemiológica que consignó edad, consumo de drogas, hacinamiento, entre otros. Resultados: La prevalencia del agente fue de 16,4% en reclusos del CDP de Arica, resultado menor a lo reportado en otros estudios similares. Conclusiones: Conocer la realidad de la prevalencia de esta ITS y algunos factores de riesgo asociados a la situación de privación de la libertad en una zona tri-fronteriza del norte de Chile, contribuye a las propuestas de programas de prevención en esta población vulnerable y de riesgo.

Abstract Background: Sex workers, people with drug addiction, early onset of sexual activity population, and criminal population, are considered the groups most at risk of contracting sexually transmitted infections (STIs). Aim: To determine the prevalence of infection by Neisseria gonorrhoeae in inmates of the Preventive Detention Center (CDP) at Arica and Parinacota Region, Chile. The Scientific Ethical Committee of Universidad de Tarapacá approved this study. Method: 140 inmates participated, who voluntarily agreed to be part of the study and signed an informed consent. A sample of urethral meatus was taken to investigate N. gonorrhoeae, and an epidemiological survey was applied, which included age, drug use, overcrowding, among others. Results: The prevalence of the agent was 16.4% in inmates of the Arica CDP, a result lower than that reported in other similar studies. Conclusion: Knowing the reality of the prevalence of this STI and some risk factors associated with the situation of deprivation of freedom in a tri-border area of northern Chile, contributes to the proposals for prevention programs in this vulnerable and at-risk population.

An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease.

AIMS: Pompe disease is caused by pathogenic mutations in the alpha 1,4-glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype-phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability. METHODS: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology-score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule-associated protein 1A/1B-light chain 3, p62 and Bcl2-associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies. RESULTS: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology-score. High morphology-scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology-score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine-kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.-32-13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type. CONCLUSIONS: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.

Improved survival outcomes and restoration of graft-vs-leukemia effect by deferasirox after allogeneic stem cell transplantation in acute myeloid leukemia.

Deferasirox is an oral iron-chelating agent having possible antileukemia and immune modulatory effects. Few reports have evaluated deferasirox in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We investigated the impact of deferasirox after allo-HSCT in acute myeloid leukemia (AML). Of 326 consecutive patients undergoing allo-HSCT in remission, analysis of 198 patients not receiving deferasirox revealed the negative prognostic effect of hyperferritinemia (≥1000 ng/mL) before and after allo-HSCT on survival mainly due to increase in relapse. Of 276 patients with hyperferritinemia at 1 month after allo-HSCT, 128 patients (46%) received deferasirox. Deferasirox induced a faster decline in serum ferritin level with a manageable safety profile, which significantly reduced relapse rather than nonrelapse mortality, resulting in better survival compared to patients not receiving deferasirox. Of note, the deferasirox group had a significantly higher incidence of chronic graft-vs-host disease, indicating improved graft-vs-leukemia (GVL) effects evidenced by the presence of suppressed regulatory T cells and sustained higher proportion of NK cells in peripheral blood. This study firstly demonstrates the improved survival and restoration of GVL effects of patients with AML by deferasirox, which also clarifies the detrimental effect of hyperferritinemia through after allo-HSCT.

An air-liquid interphase approach for modeling the early embryo-maternal contact zone.

We developed an air-liquid interphase culture procedure for mammalian oviduct epithelial cells leading to the formation of functional epithelial tissues, which generate oviduct fluid surrogates. These in vitro oviduct epithelia can be co-cultured with living zygotes and enable embryonic development up to the blastocyst stage without addition of embryo culture medium. The described strategy is broadly applicable to analyze early embryo-maternal interactions under standardized in vitro conditions.

Impact of oral consumption of heat-treated Bacteroides xylanisolvens DSM 23964 on the level of natural TFα-specific antibodies in human adults.

It is now generally accepted that the human body exists in close synergy with the gut microbiome and that this cross-talk plays an essential role in human health and disease. One facet from the many interactions between the microbiome and the immune system is the induction of natural antibodies to commensal bacterial glycans, such as blood group antigens, the alpha-Gal epitope or the Thomsen-Friedenreich (TFα) antigen. Since we have observed that certain species of the commensal genus Bacteroides express the TFα antigen, we examined whether the oral dietary supplementation of a pasteurised Bacteroides xylanisolvens strain might be able to enhance the level of natural anti-TFα antibodies in healthy adults. The data obtained from a double-blind, placebo-controlled study involving 140 healthy volunteers and lasting 8 weeks revealed that the oral uptake of this strain was indeed able to increase the level of TFα-specific immunoglobulin M serum antibodies. The effect was dose-dependent but remained - at any doses - within the physiological range determined before intervention. Furthermore, the effect reverted after stopping the intake. The results support the idea of the microbiome inducing the generation of systemic antigen-specific antibodies against sugar epitopes. They also demonstrate the possibility to modulate essential regulatory or defence processes through dietary supplementation of selected commensal bacteria with the aim to assist human health.

Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium.

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp).

HLA-A2 reactive antibodies in a patient who types as HLA-A2: The importance of high resolution typing and epitope-based antibody analysis.

This report describes a case of a highly sensitized patient who had serum antibodies reacting with HLA-A2 but whose phenotype included HLA-A2. The determination of HLA mismatch acceptability at the antigen level was problematic, but high-resolution HLA typing information and epitope-based antibody specificity analysis based on the nonself-self paradigm of HLA epitope immunogenicity have provided a solution. This case supports the concept that HLA typing at the allele level offers a better approach to identifying suitable donors for sensitized patients.

A combination of palm oil tocotrienols and citrus peel polymethoxylated flavones does not influence elevated LDL cholesterol and high-sensitivity C-reactive protein levels.

BACKGROUND/OBJECTIVES: Lipid-lowering and anti-inflammatory effects have been individually described for tocotrienols (TTs) and polymethoxylated flavones (PMFs). This study investigated low-density lipoprotein-cholesterol (LDL-C)- and high-sensitivity C-reactive protein (hsCRP)-reducing effects of combined TT-PMF treatment in low doses in hypercholesterolemic individuals with subclinical inflammation. SUBJECTS/METHODS: In the double-blind, placebo-controlled study, 240 Caucasians with LDL-C ⩾3.36 mmol/l and hsCRP ⩾1 mg/l were enrolled and randomized into group S1 (12 mg/day TT and 103 mg/day PMF), group S2 (27 mg/day TT and 32 mg/day PMF) or placebo. RESULTS: Twenty-three subjects dropped out of the study, 13 were excluded from the analysis because of lack of compliance. A total of 204 subjects per-protocol analysis were included. After 12 weeks of treatment, no significant differences in LDL-C levels (primary outcome) were observed between groups. LDL-C levels significantly decreased in all intervention groups (S1: -5.2%, S2: -4.8% and P: -4.2%). Total cholesterol and hsCRP (secondary outcome) did not change significantly. CONCLUSIONS: PMF-TT supplements had no effect beyond that of placebo on elevated LDL-C and hsCRP levels.

CLIC4 regulates TGF-ß-dependent myofibroblast differentiation to produce a cancer stroma.

Cancer stroma has a profound influence on tumor development and progression. The conversion of fibroblasts to activated myofibroblasts is a hallmark of reactive tumor stroma. Among a number of factors involved in this conversion, transforming growth factor (TGF)-ß has emerged as a major regulator. CLIC4, an integral protein in TGF-ß signaling, is highly upregulated in stroma of multiple human cancers, and overexpression of CLIC4 in stromal cells enhances the growth of cancer xenografts. In this study, we show that conditioned media from tumor cell lines induces expression of both CLIC4 and the myofibroblast marker alpha smooth muscle actin (α-SMA) in stromal fibroblasts via TGF-ß signaling. Genetic ablation of CLIC4 in primary fibroblasts prevents or reduces constitutive or TGF-ß-induced expression of α-SMA and extracellular matrix components that are markers of myofibroblasts. CLIC4 is required for the activation of p38 map kinase by TGF-ß, a pathway that signals myofibroblast conversion in stromal cells. This requirement involves the interaction of CLIC4 with PPM1a, the selective phosphatase of activated p38. Conditioned media from fibroblasts overexpressing CLIC4 increases tumor cell migration and invasion in a TGF-ß-dependent manner and promotes epithelial to mesenchymal transition indicating that high stromal CLIC4 serves to enhance tumor invasiveness and progression. Thus, CLIC4 is significantly involved in the development of a nurturing tumor microenvironment by enhancing TGF-ß signaling in a positive feedback loop. Targeting CLIC4 in tumor stroma should be considered as a strategy to mitigate some of the tumor enhancing effects of the cancer stroma.

Smokers run increased risk of developing anti-natalizumab antibodies.

BACKGROUND: Smoking may contribute to the induction of neutralizing antibodies to interferon ß-1a. OBJECTIVE: In this study, we aimed to investigate the influence of smoking on the risk of developing antibodies to natalizumab, another biological drug in the treatment of multiple sclerosis. METHODS: This report is based on 1338 natalizumab-treated multiple sclerosis patients included in either of two Swedish case-control studies in which information on smoking habits was collected. Using logistic regression, patients with different smoking habits were compared regarding risk of developing anti-natalizumab antibodies, by calculating odds ratios with 95% confidence intervals. RESULTS: Compared with nonsmokers, the odds ratio of developing anti-natalizumab antibodies was 2.4 (95% CI 1.2-4.4) for patients who smoked at the time of screening, and a significant trend showed higher risk of developing antibodies with higher intensity of smoking. When smoking within two years prior to screening was considered, the odds ratio of developing anti-natalizumab antibodies was 2.7 (1.5-5.1). INTERPRETATIONS: The finding strengthens our hypothesis of the lungs as immune-reactive organs on irritation in relation to autoimmune responses, and may also be of clinical relevance since antibodies against natalizumab abrogate the therapeutic effect of the treatment.

Treatment of metastatic colorectal cancer with cetuximab: influence on the quality of life.

BACKGROUND: Epidermal Growth Factor Receptor (EGFR) antibodies are innovative anti-cancer drugs prolonging survival in metastatic colocrectal cancer. However, due to adverse drug reactions, patients develop acneform skin toxicities. We hypothesized that the skin reaction leads to a decline in general (QOL) and dermatological health related quality of life (HQOL). Furthermore, we aimed at evaluating predictors for QOL and HQOL to improve individual adjustment of therapy. METHODS: 40 outpatients with metastatic colocrectal cancer were involved in this study. According to their KRAS status, patients were allocated to 2 groups: The CTCX group (n = 20; KRAS wild-type) was treated with the EGFR-antibody Cetuximab plus chemotherapy, the CT group (n = 20; KRAS mutation) was receiving chemotherapy only. Psychological assessment consisted of questionaires to evaluate QOL and HQOL, depression, coping-styles, health beliefs and the patient´s personality. RESULTS: Between the two groups, no significanct difference in QOL was found, QOL remained stable over the course of treatment. Yet, the severity of the skin reactions had a significant influence on HQOL. Internal health beliefs and high compliance were found to be protective factors, while passive coping strategies, depression and the personality trait neuroticism were identified as risk factors. DISCUSSION: Interdisciplinary cooperation between medical professionals and psycho-oncologists is strongly recommended to encourage patients to embark on and to retain EGFR-antibody therapy. If risk factors are present, psycho-oncological therapy should focus on the minimization of depression and on the development of active coping strategies.

Sexing domestic chicken before hatch: a new method for in ovo gender identification.

Male chicks are an unwanted by-product when producing laying hens. The common practice to kill them directly after they have hatched gives rise to ethical concerns worldwide. The aim of this study was to develop an endocrine method to determine the sex of domestic chicken before hatch. On Days 7 to 10 of incubation, the allantoic fluid from brown layers' eggs (n = 750) was analyzed via enzyme immunoassay for their content of estradiol, estrone sulfate, and testosterone in order to detect gender differences. We successfully established a reliable method for in ovo sex identification on Day 9 of incubation by estrone sulfate measurement in the allantoic fluid. Female embryos displayed significantly higher hormone levels in the allantoic fluid than males (female: median = 0.312 ng/mL; male: median = 0.110 ng/mL; P ≤ 0.001). Our method allows the sexing of domestic chicken at a very early stage of embryonic development, even before the onset of pain perception. The possibility to eliminate eggs containing male embryos on Day 9 of incubation represents a vast improvement compared with culling day-old chicks.

Quantification of the radio-metabolites of the serotonin-1A receptor radioligand [carbonyl-11C]WAY-100635 in human plasma: an HPLC-assay which enables measurement of two patients in parallel.

[Carbonyl-(11)C]WAY-100635 is a potent and effective antagonist for the 5-HT(1A) receptor subtype. We aimed to assess the status of [carbonyl-(11)C]WAY-100635 and its main radio-metabolites, [carbonyl-(11)C]desmethyl-WAY-100635 and [carbonyl-(11)C]cyclohexanecarboxylic acid, on the basis of an improved radio-HPLC method. Common methods were characterized by preparative HPLC columns with long runtimes and/or high flow rates. Considering the short half-life of C-11, we developed a more rapid and solvent saving HPLC assay, allowing a fast, efficient and reliable quantification of these major metabolites.

Oxytocin plasma concentrations after single intranasal oxytocin administration - a study in healthy men.

The neuropeptide oxytocin has become a subject of great interest in studies investigating human social cognition. Single intranasal administration of the hormone has been reported to have positive behavioral effects, such as increasing trust or facilitating social approach, 45-80 min after administration. However, little is still known about the long-term pharmacokinetics of oxytocin nasal spray application in humans. This study addressed the question how long oxytocin plasma levels remain elevated following nasal spray administration. Another goal was to examine the influence of oxytocin administration on endogenous steroid hormones since such alterations might modulate social behavior via an indirect way. Eight healthy Caucasian men were challenged with a single intranasal application of 26 international units of oxytocin. Changes in oxytocin blood plasma levels, as well as steroid hormone levels of progesterone, testosterone and estradiol were assessed at 5 consecutive time points over a period of 3.5 h (-5, +30, +90, +150, +210 min relative to oxytocin administration). Results gave evidence for a substantial rise of oxytocin plasma levels 30 min after intranasal administration, observed in 7 of 8 participants. Group mean oxytocin plasma level was found to have returned to baseline already 90 min post administration, though in some individuals the plasma levels was still elevated relative to sampling at post 150 min. Steroid hormone analyses yielded a slight augmentation of endogenous testosterone levels 210 min after oxytocin administration. Our data confirms previous findings that oxytocin administered as a nasal spray enters the blood circulation, elevating oxytocin plasma levels for a limited time. Our findings suggest that this time window differs between individuals, but that, for the used dose, it does not extend beyond 150 min post administration. The data further provides preliminary evidence that intranasal oxytocin has an enhancing effect on testosterone in healthy men.