Quantifying Isoniazid Levels in Small Hair Samples: A Novel Method for Assessing Adherence during the Treatment of Latent and Active Tuberculosis.

BackgroundTuberculosis (TB) is the leading cause of death from an infectious pathogen worldwide and the most prevalent opportunistic infection in people living with HIV. Isoniazid preventive therapy (IPT) reduces the incidence of active TB and reduces morbidity and mortality in HIV-infected patients independently of antiretroviral therapy. However, treatment of latent or active TB is lengthy and inter-patient variability in pharmacokinetics and adherence common. Current methods of assessing adherence to TB treatment using drug levels in plasma or urine assess short-term exposure and pose logistical challenges. Drug concentrations in hair assess long-term exposure and have demonstrated pharmacodynamic relevance in HIV.MethodsA large hair sample from a patient with active TB was obtained for assay development. Methods to pulverize hair and extract isoniazid were optimized and then the drug detected by liquid chromatography/ tandem mass spectrometry (LC/MS-MS). The method was validated for specificity, accuracy, precision, recovery, linearity and stability to establish the assay's suitability for therapeutic drug monitoring (TDM). Hair samples from patients on directly-observe isoniazid-based latent or active TB therapy from the San Francisco Department of Public Health TB clinic were then tested.ResultsOur LC/MS-MS-based assay detected isoniazid in quantities as low as 0.02ng/mg using 10-25 strands hair. Concentrations in spiked samples demonstrated linearity from 0.05-50ng/mg. Assay precision and accuracy for spiked quality-control samples were high, with an overall recovery rate of 79.5%. In 18 patients with latent or active TB on treatment, isoniazid was detected across a wide linear dynamic range.ConclusionsAn LC-MS/MS-based assay to quantify isoniazid levels in hair with performance characteristics suitable for TDM was developed and validated. Hair concentrations of isoniazid assess long-term exposure and may be useful for monitoring adherence to latent or active TB treatment in the setting of HIV

Mécanisme de recrutement des leucocytes dans le cerveau

Les leucocytes sont connus pour jouer des rôles autant bénéfiques que néfastes dans le système nerveux central. La compréhension de leur mécanisme de recrutement est donc importante afin de contrôler leur circulation à travers la barrière hémato-encéphalique. De façon générale, l'adhésion forte est reconnue comme étant une étape clé de ce recrutement. Les principales actrices qui y sont impliquées sont les chimiokines et les intégrines. Cependant, l'identité de ces dernières peut changer selon le tissu, le stimulus et la nature des leucocytes recrutés. Dans ce travail, nous nous sommes intéressé à une population de leucocytes principalement composée de granulocytes : les leucocytes en forme de bâtonnets. Notre objectif principal a été de caractériser le mécanisme d'adhésion de ces cellules, dans le cerveau, en conditions inflammatoires via l'utilisation d'anticorps neutralisants ou d'animaux déficients pour les gènes d'intérêt. Notre hypothèse a été que l'intégrine αMβ2, via sa liaison avec ICAM-1, ainsi que l'une des chimiokines liant CXCR2, sont importantes pour adhésion des granulocytes en réponse à différents produits bactériens (la toxine pertussique (PTX) et le lipopolysaccharide (LPS)) et durant l'encéphalomyélite auto-immune expérimentale (EAE). Afin de valider cette idée, nous avons, dans un premier temps, déterminé si l'expression spatio-temporelle d'ICAM-1 est régulée par la PTX et/ou le LPS et si son absence ainsi que la neutralisation d'αMβ2 influencent le recrutement des granulocytes. En second lieu, nous avons déterminé quel ligand de CXCR2 est le plus fortement exprimé dans ces conditions et vérifié si la neutralisation de cette chimiokine, CXCL1, affecte l'adhésion des granulocytes. Nos résultats ont démontré qu'ICAM-1 peut effectivement être régulée par le LPS et la PTX, qu'en réponse à cette dernière toxine, αMβ2 semble être l'unique intégrine responsable de l'adhésion des leucocytes bâtonnets et qu'elle joue son rôle via, entre autre, ICAM-1. De plus, il s'avère que CXCL1 et CXCR2 sont importants dans l'adhésion des granulocytes en réponse à la PTX et au LPS. Finalement, non seulement la neutralisation de CXCL1 diminue cette même adhésion durant l'EAE, mais réduit également la gravité de la maladie. En conclusion, dans ce projet, nous avons contribué à mieux comprendre le mécanisme de recrutement des granulocytes dans le cerveau sous différentes conditions inflammatoires

Étude des superoxyde dismutases (SOD) dans l'oviducte bovin

L'oviducte est important dans le transport, la maturation et la fécondation des gamètes mâles et femelles. Il est connu qu'un équilibre entre les antioxydants et les dérivés actifs de l'oxygène (ROS) est essentiel à la réalisation de ces processus reproducteurs. Cependant, peu de connaissances sont acquises sur les antioxydants présents dans l'oviducte. Les superoxyde dismutases, soit la forme cytosolique (Cu, ZnSOD), la forme mitochondriale (MnSOD) et la forme extracellulaire (EC-SOD) sont des antioxydants enzymatiques qui neutralisent l'anion superoxyde (O2"), un ROS. Mon hypothèse est que les SOD sont régulées de façon précise dans l'oviducte ainsi que durant le cycle oestral bovin pour assurer le succès reproducteur. L'immunobuvardage et l'immunohistochimie ont servi à caractériser les formes protéiques de la MnSOD et de la Cu, ZnSOD. Nos résultats montrent que ces deux formes de SOD ont des patrons d'expression qui varient de façon spatio-temporelle dans l'oviducte bovin. Cela suggère que la forme cytosolique (Cu, ZnSOD) et mitochondriale (MnSOD) de la superoxyde dismutase jouent des rôles essentiels dans l'oviducte et fort probablement dans le processus de la maturation finale des gamètes mâles ainsi que dans la fécondation

THE EFFECT OF INFLATION, INTEREST RATE, EXCHANGE RATE AND GROSS DOMESTIC PRODUCT GROWTH ON COMPOSITE STOCK PRICE INDEX (Study at Indonesia Stock Exchange Period of 2010-2019)

The purpose of this study is to determine the effect of inflation, interest rate, exchange rate, and gross domestic product growth on composite stock price index. The research design used in this study is multiple linear regression. Pearson correlation test, F-test and t-test are used in hypotesis testing. To have a more reliable result, these data undergone several tests, which are descriptive statistics, boxplot statistics, normality, heteroscedasticity, multicollinearity, and autocorrelation. The results of this study showed that exchange rate and gross domestic product growth significantly affect composite stock price index. Inflation and interest rate were insignificant in explaining composite stock price index. Coefficient of determination is 37.2%. It shows that 37.2% variation of dependent variable can explained by variation of four independent variables in this research, while the rest of 62.8% explained by the other variables which are not scrutinized in this study. Keywords:composite stock price index, inflation, interest rate, exchange rate, growth gross domestic product

Patient Perspectives of the Doctor-at-Home Service

Introduction. Home health care has been established as an effective model for reducing mortality in the elderly. The Doctor-at-Home Service at the Community Health Centers of Burlington (CHCB) has offered home health care to Burlington residents since January 2015. Dr. Karen Sokol, MD, alone provides care to 176 patients at their homes, including at-home palliative care. CHCB hope to expand this program by hiring more providers. Objective. To understand the impact of the Doctor-at-Home Service from the pa- tients’ perspective. Methods. A survey was administered to a cohort of eighteen patients over an 8- week period and addressed topics such as barriers to healthcare, benefits, and costs associated with doctor-at-home programs. A theme analysis on the responses was then conducted to reflect patient opinions. Available summary data describing the pa- tient population was also analyzed. Results. The Doctor- at- Home program serves patients ranging from 26 to 100 years old, with the majority of the patient population comprised of senior citizens. Prior to at home care, patients faced barriers such as lack of transportation, negative past experi- ences, anxiety, and distance from relatives. Four main themes from patient responses were physician-patient relationship, convenience, quality of care, and environment of care. Discussion. Evidence is compelling that there is a desire and need for an exten- sion of the Doctor-at-Home program to reach additional patients. Doctor-at-Home pro- grams could eliminate identified barriers and provide quality care to patients, especially those with specific barriers to access.https://scholarworks.uvm.edu/comphp_gallery/1256/thumbnail.jp

HE 0430-2457: a post merger extremely low-mass pre-white dwarf in a wide binary posing as an extreme horizontal branch star

We report the discovery of HE 0430-2457, the first extremely low-mass pre-white dwarf (ELM pre-WD) in a long period binary (P = 771 +- 3 d). The spectroscopic parameters of the primary are determined to be Teff = 26200 +- 1500 K and logg = 5.40 +- 0.35, placing it in the region occupied by core He-burning hot subdwarf B stars. By comparing the spectroscopic parameters of the K-type companion to stellar models, and using the mass ratio, the mass of the hot primary is determined to be 0.23 Msun. Given that this is too low for core He-burning, the primary in HE 0430-2457 is not an EHB star but a pre WD of the ELM type. As the lifetime of ELM pre-WDs in this region of the HR diagram populated by EHBs is thought to be very short, they are not considered to be part of the observed EHBs. However, the discovery of this system indicates that the percentage of ELM pre-WDs in the observed EHB population might be higher than previously thought. Binary evolution models indicate that HE 0430-2457 is likely formed by a merger of the inner binary in a hierarchical triple system.Comment: 5 pages, 3 figures, Accepted for publication in MNRA