Associations of CD4 Cell Count Measures With Infection-Related and Infection-Unrelated Cancer Risk Among People With HIV.

BACKGROUND: People with HIV are at higher risk of infection-related cancers than the general population, which could be due, in part, to immune dysfunction. Our objective was to examine associations between 4 CD4 count measures as indicators of immune function and infection-related and infection-unrelated cancer risk. SETTING: We conducted a cohort study of adults with HIV who were diagnosed with cancer in Ontario, Canada. Incident cancers were identified from January 1, 1997 to December 31, 2020. METHODS: We estimated adjusted hazard ratios (aHR) for the associations between CD4 measures (baseline CD4, nadir CD4, time-updated CD4, time-updated CD4:CD8) and cancer incidence rates using competing risk analyses, adjusted for socio-demographic factors, history of hepatitis B or C infection, baseline viral load, smoking, and alcohol use. RESULTS: Among 4771 people with HIV, contributing 59,111 person-years of observation, a total of 549 cancers were observed. Low baseline CD4 (<200 cells/µL) (aHR 2.08 [95% CI: 1.38 to 3.13], nadir (<200 cells/µL) (aHR 2.01 [95% CI: 1.49 to 2.71]), low time-updated CD4 (aHR 3.52 [95% CI: 2.36 to 5.24]) and time-updated CD4:CD8 ratio (<0.4) (aHR 2.02 [95% CI: 1.08 to 3.79]) were associated with an increased rate of infection-related cancer. No associations were observed for infection-unrelated cancers. CONCLUSIONS: Low CD4 counts and indices were associated with increased rates of infection-related cancers among people with HIV, irrespective of the CD4 measure used. Early diagnosis and linkage to care and high antiretroviral therapy uptake may lead to improved immune function and could add to cancer prevention strategies such as screening and vaccine uptake.

Trends in infection-related and infection-unrelated cancer incidence among people with and without HIV infection in Ontario, Canada, 1996-2020: a population-based matched cohort study using health administrative data.

BACKGROUND: People with HIV infection are at higher risk for certain cancers than the general population. We compared trends in infection-related and infection-unrelated cancers among people with and without HIV infection. METHODS: We conducted a retrospective population-based matched cohort study of adults with and without HIV infection using linked health administrative databases in Ontario, Canada. Participants were matched on birth year, sex, census division (rurality), neighbourhood income quintile and region of birth. We followed participants from cohort entry until the earliest of date of cancer diagnosis, date of death, Nov. 1, 2020, or date of loss to follow-up. Incident cancers identified from Jan. 1, 1996, to Nov. 1, 2020, were categorized as infection-related or-unrelated. We examined calendar periods 1996-2003, 2004-2011 and 2012-2020, corresponding to the early combination antiretroviral therapy (cART), established cART and contemporary cART eras, respectively. We used competing risk analyses to examine trends in cumulative incidence by calendar period, age and sex, and cause-specific hazard ratios (HRs). RESULTS: We matched 20 304 people with HIV infection to 20 304 people without HIV infection. A total of 2437 cancers were diagnosed, 1534 (62.9%) among infected people and 903 (37.0%) among uninfected people. The risk of infection-related cancer by age 65 years for people with HIV infection decreased from 19.0% (95% confidence interval [CI] 15.6%-22.3%) in 1996-2011 to 10.0% (95% CI 7.9%-12.1%) in 2012-2020. Compared to uninfected people, those with HIV infection had similar HRs of infection-unrelated cancer but increased rates of infection-related cancer, particularly among younger age groups (25.1 [95% CI 13.2-47.4] v. 1.9 [95% CI 1.0-3.7] for age 18-39 yr v. ≥ 70 yr); these trends were consistent when examined by sex.Interpretation: We observed significantly higher rates of infection-related, but not infection-unrelated, cancer among people with HIV infection than among uninfected people. The elevated rate of infection-related cancer in 2012-2020 highlights the importance of early and sustained antiretroviral therapy along with cancer screening and prevention measures.

Cancer Risk among Adults Living with HIV in Ontario.

Cancer is an important comorbidity and healthcare concern for people living with the human immunodeficiency virus (HIV). Researchers have quantified the burden of cancer among people living with HIV in Ontario using administrative and registry-linked data held at ICES. Findings showed that although cancer incidence has declined over time, people living with HIV remain at a greater risk for cancers with infectious causes compared with HIV-negative people. There is a need for comprehensive HIV care that includes cancer prevention strategies.

Synthetic Approaches of Epoxysuccinate Chemical Probes.

Synthetic chemical probes are powerful tools for investigating biological processes. They are particularly useful for proteomic studies such as activity-based protein profiling (ABPP). These chemical methods initially used mimics of natural substrates. As the techniques gained prominence, more and more elaborate chemical probes with increased specificity towards given enzyme/protein families and amenability to various reaction conditions were used. Among the chemical probes, peptidyl-epoxysuccinates represent one of the first types of compounds used to investigate the activity of the cysteine protease papain-like family of enzymes. Structurally derived from the natural substrate, a wide body of inhibitors and activity- or affinity-based probes bearing the electrophilic oxirane unit for covalent labeling of active enzymes now exists. Herein, we review the literature regarding the synthetic approaches to epoxysuccinate-based chemical probes together with their reported applications, from biological chemistry and inhibition studies to supramolecular chemistry and the formation of protein arrays.

The burden of cancer among people living with HIV in Ontario, Canada, 1997-2020: a retrospective population-based cohort study using administrative health data.

BACKGROUND: With combination antiretroviral therapy (ART) and increased longevity, cancer is a leading cause of morbidity among people with HIV. We characterized trends in cancer burden among people with HIV in Ontario, Canada, between 1997 and 2020. METHODS: We conducted a population-based, retrospective cohort study of adults with HIV using linked administrative health databases from Jan. 1, 1997, to Nov. 1, 2020. We grouped cancers as infection-related AIDS-defining cancers (ADCs), infection-related non-ADCs (NADCs) and infection-unrelated cancers. We calculated age-standardized incidence rates per 100 000 person-years with 95% confidence intervals (CIs) using direct standardization, stratified by calendar period and sex. We also calculated limited-duration prevalence. RESULTS: Among 19 403 adults living with HIV (79% males), 1275 incident cancers were diagnosed. From 1997-2000 to 2016- 2020, we saw a decrease in the incidence of all cancers (1113.9 [95% CI 657.7-1765.6] to 683.5 [95% CI 613.4-759.4] per 100 000 person-years), ADCs (403.1 [95% CI 194.2-739.0] to 103.8 [95% CI 79.2-133.6] per 100 000 person-years) and infection-related NADCs (196.6 [95% CI 37.9-591.9] to 121.9 [95% CI 94.3-154.9] per 100 000 person-years). The incidence of infection-unrelated cancers was stable at 451.0 per 100 000 person-years (95% CI 410.3-494.7). The incidence of cancer among females increased over time but was similar to that of males in 2016-2020. INTERPRETATION: Over a 24-year period, the incidence of cancer decreased overall, largely driven by a considerable decrease in the incidence of ADC, whereas the incidence of infection-unrelated cancer remained unchanged and contributed to the greatest burden of cancer. These findings could reflect combination ART-mediated changes in infectious comorbidity and increased life expectancy; targeted cancer screening and prevention strategies are needed.

Feasibility analysis for the development of a video-assisted thoracoscopic (VATS) lobectomy 23-hour recovery pathway.

Background: Video-assisted thoracoscopic (VATS) lobectomy has been demonstrated to offer several benefits over open surgery. The purpose of this study was to assess the feasibility and safety of an ultra-fast-track 23-hour recovery pathway for VATS lobectomy. Methods: A prospectively maintained institutional database was queried for patients who underwent VATS lobectomy from 2006 to 2016 at the McGill University Health Centre in Montreal, Quebec, and data were supplemented with focused chart review. Patients discharged with a length of stay (LOS) of 23 hours or less were compared with those with an LOS of 2 days or more. Logistic regression was performed to identify predictors of LOS of 23 hours or less. Results: Two hundred and five patients were included in the study. Perioperative 30-day mortality for our cohort was 0% and the major complication rate was 8.3%. The median LOS was 3 days (interquartile range [IQR] 2-4 d). Thirty-four patients were discharged within 23 hours and none of them required readmission; 171 patients were discharged on postoperative day 2 or later and 9 of them (5.3%) required readmission (p = 0.36). The proportion of patients discharged within 23 hours increased in 2016 compared with previous years (25.8% v. 12.0%, p = 0.05). Patients discharged within 23 hours had shorter chest tube duration (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.09-0.46, p < 0.001), lower clinical stage disease (stages II-III v. stage I OR 0.07, 95% CI 0.01-0.52, p = 0.011), lower pathologic stage lesions (stages II-III v. stage I OR 0.26, 95% CI 0.07-0.91, p = 0.035), fewer surgical complications (OR 0.04, 95% CI 0.01-0.30, p = 0.002) and shorter operative time (surgery duration > 120 min OR 0.42, 95% CI 0.18-0.95, p = 0.04). Our exploratory prediction modelling showed that chest tube duration, clinical stage and surgeon were the most influential predictors of discharge within 23 hours. Conclusion: The only preoperative factors that predicted shorter LOS in our cohort were clinical stage and surgeon. A significant proportion of patients can be discharged safely by adopting a VATS lobectomy 23-hour enhanced recovery pathway.

Contexte: Il a été démontré que la lobectomie par chirurgie thoracique vidéoassistée (CTVA) offre plusieurs avantages comparativement à la chirurgie ouverte. La présente étude avait pour but d'évaluer la faisabilité et la sûreté d'un protocole de récupération ultrarapide en 23 heures pour la lobectomie par CTVA. Méthodes: Nous avons extrait d'une base de données d'établissement maintenue de manière prospective des données sur les patients ayant subi une lobectomie par CTVA entre 2006 et 2016 au Centre universitaire de santé McGill à Montréal (Québec), complétées par un examen ciblé des dossiers. Les patients ayant reçu leur congé après une hospitalisation de 23 heures ou moins ont été comparés à ceux dont l'hospitalisation avait duré 2 jours ou plus. Nous avons ensuite mis en évidence les facteurs prédictifs d'une hospitalisation de 23 heures ou moins par une analyse de régression logistique. Résultats: Deux cent cinq patients ont été inclus dans l'étude. La mortalité périopératoire dans les 30 jours suivant l'intervention était de 0 % dans notre cohorte, et le taux de complications majeures était de 8,3 %. La durée d'hospitalisation médiane était de 3 jours (écart interquartile [EI] 2 à 4 jours). Trente-quatre patients ont reçu leur congé dans les 23 heures suivant l'intervention, et aucun n'a dû être réhospitalisé; comparativement, 171 patients ont reçu leur congé au deuxième jour ou après, et 9 d'entre eux (5,3 %) ont dû être réhospitalisés (p = 0,36). Le pourcentage de patients ayant reçu leur congé dans les 23 heures a augmenté en 2016 par rapport aux années précédentes (25,8 % c. 12,0 %, p = 0,05). Les patients au congé dans les 23 heures conservaient leur drain thoracique moins longtemps (rapport de cotes [RC] 0,20, intervalle de confiance [IC] de 95 % 0,09 à 0,46, p < 0,001); leur stade clinique était moins élevé (stades II à III c. stade I ­ RC 0,07, IC de 95 % 0,01 à 0,52, p = 0,011); le stade pathologique de leurs lésions était plus faible (stades II à III c. stade I ­ RC 0,26, IC de 95 % 0,07 à 0,91, p = 0,035); ils avaient moins de complications chirurgicales (RC 0,04, IC de 95 % 0,01 à 0,30, p = 0,002); et la durée de leur intervention était plus courte (durée de la chirurgie > 120 minutes ­ RC 0,42, IC de 95 % 0,18 à 0,95, p = 0,04). Notre modèle prédictif exploratoire a montré que le délai avant le retrait du drain thoracique, le stade clinique et le chirurgien était les facteurs prédictifs les plus importants du congé dans les 23 heures. Conclusion: Les seuls facteurs préopératoires permettant de prédire une hospitalisation plus courte dans notre cohorte étaient le stade clinique et le chirurgien. Un pourcentage important des patients peuvent recevoir leur congé sans danger si on suit un protocole de récupération optimisée en 23 heures après une lobectomie par CTVA.

Synthesis, Characterization, and Biologic Activity of New Acyl Hydrazides and 1,3,4-Oxadiazole Derivatives.

Starting from isoniazid and carboxylic acids as precursors, thirteen new hydrazides and 1,3,4-oxadiazoles of 2-(4-substituted-phenoxymethyl)-benzoic acids were synthesized and characterized by appropriate means. Their biological properties were evaluated in terms of apoptosis, cell cycle blocking, and drug metabolism gene expression on HCT-8 and HT-29 cell lines. In vitro antimicrobial tests were performed by the microplate Alamar Blue assay for the anti-mycobacterial activities and an adapted agar disk diffusion technique for other non-tubercular bacterial strains. The best antibacterial activity (anti-Mycobacterium tuberculosis effects) was proved by 9. Compounds 7, 8, and 9 determined blocking of G1 phase. Compound 7 proved to be toxic, inducing apoptosis in 54% of cells after 72 h, an effect that can be predicted by the increased expression of mRNA caspases 3 and 7 after 24 h. The influence of compounds on gene expression of enzymes implicated in drug metabolism indicates that synthesized compounds could be metabolized via other pathways than NAT2, spanning adverse effects of isoniazid. Compound 9 had the best antibacterial activity, being used as a disinfectant agent. Compounds 7, 8, and 9, seemed to have antitumor potential. Further studies on the action mechanism of these compounds on the cell cycle may bring new information regarding their biological activity.

Ban on menthol-flavoured tobacco products predicts cigarette cessation at 1 year: a population cohort study.

OBJECTIVES: The province of Ontario, Canada, banned the use of menthol-flavoured tobacco products as of 1 January 2017. The long-term impact of a menthol ban on smoking behaviour has not been previously evaluated. METHODS: Population cohort study with baseline survey conducted September-December 2016 and follow-up January-August 2018 among residents of Ontario, Canada, 16 years old and over who reported current smoking (past 30 days) at baseline survey and completed follow-up (n=913) including 187 reporting smoking menthol cigarettes daily, 420 reported smoking menthol cigarettes occasionally, and 306 were non-menthol cigarette smokers. Relative rates of making a quit attempt and being a non-smoker at follow-up were estimated with Poisson regression controlling for smoking and demographic characteristics at baseline. RESULTS: At follow-up, 63% of daily menthol smokers reported making a quit attempt since the ban compared with 62% of occasional menthol smokers and 43% of non-menthol smokers (adjusted relative rate (ARR) for daily menthol smokers compared with non-menthol smokers: 1.25; 95% CI 1.03 to 1.50). At follow-up, 24% of daily menthol smokers reported making a quit since the ban compared with 20% of occasional menthol smokers and 14% of non-menthol smokers (ARR for daily menthol smokers compared with non-menthol smokers: 1.62; 95% CI 1.08 to 2.42). CONCLUSIONS: The study found higher rates of quitting among daily and occasional menthol smokers in Ontario 1 year after the implementation of a menthol ban compared with non-menthol smokers. Our findings suggest that restrictions on menthol may lead to substantial improvements in public health.

Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects.

Targeting the dynamic tumor immune microenvironment (TIME) can provide effective therapeutic strategies for cancer. Neutrophils are the predominant leukocyte population in mice and humans, and mounting evidence implicates these cells during tumor growth and metastasis. Neutrophil extracellular traps (NETs) are networks of extracellular neutrophil DNA fibers that are capable of binding tumor cells to support metastatic progression. Here we demonstrate for the first time that circulating NET levels are elevated in advanced esophageal, gastric and lung cancer patients compared to healthy controls. Using pre-clinical murine models of lung and colon cancer in combination with intravital video microscopy, we show that NETs functionally regulate disease progression and that blocking NETosis through multiple strategies significantly inhibits spontaneous metastasis to the lung and liver. Further, we visualize how inhibiting tumor-induced NETs decreases cancer cell adhesion to liver sinusoids following intrasplenic injection - a mechanism previously thought to be driven primarily by exogenous stimuli. Thus, in addition to neutrophil abundance, the functional contribution of NETosis within the TIME has critical translational relevance and represents a promising target to impede metastatic dissemination.

Epigallocatechin-3-O-gallate, the main green tea component, is toxic to Saccharomyces cerevisiae cells lacking the Fet3/Ftr1.

Epigallocatechin-3-O-gallate (EGCG), the main green tea component, is intensively studied for its anti-oxidant, anti-inflammatory, anti-microbial and anti-cancer effects. In the present study, a screen on a Saccharomyces cerevisiae gene deletion library was performed to identify conditions under which EGCG had deleterious rather than beneficial effects. Two genes were identified whose deletion resulted in sensitivity to EGCG: FET3 and FTR1, encoding the components of the Fet3/Ftr1 high-affinity iron uptake system, also involved in Cu(I)/Cu(II) balance on the surface of yeast cells. The presence of EGCG in the growth medium induced the production of Cu(I), with deleterious effects on fet3Δ and ftr1Δ cells. Additionally, when combined, physiological surpluses of Cu(II) and EGCG acted in synergy not only against fet3Δ and ftr1Δ, but also against wild type cells, by generating surplus Cu(I) in the growth medium. The results imply that caution should be taken when combining EGCG-rich beverages/nutraceuticals with copper-rich foods.

Same day discharge for benign laparoscopic hiatal surgery: a feasibility analysis.

BACKGROUND: Advances in minimally invasive surgery and the development of enhanced recovery pathways have favored the spread of day-surgery programs. Despite laparoscopic approaches being accepted as the standard of care for benign hiatal diseases, safety and feasibility of same day discharges for laparoscopic hiatal surgeries other than fundoplication has yet to be established. OBJECTIVE: This study aimed to assess the feasibility of same day discharge for primary and revisional laparoscopic hiatal surgeries including paraesophageal hernia repairs (PEHR), fundoplication for reflux, and Heller myotomy (±diverticulectomy). METHODS: A retrospective cohort study including all patients undergoing elective laparoscopic hiatal procedures in the division of Thoracic surgery between 2011 and 2016 at McGill University Health Centre was performed. Planned day-surgery (DAYCASE) was compared to planned inpatient (INPATIENT) cohorts with respect to operative and postoperative outcomes, length of stay, readmission, and emergency room visits. RESULTS: A total of 261 patients were identified, 161 female (62%); median age 62 (20). The case distribution was: PEHR (123; 47.1%), Heller myotomy (94;36%, 7 diverticulectomy), and fundoplication (44; 16.9%). Twenty patients had revisional procedures (7.7%). Same day discharge was planned in 98 cases (38%) and was successful in 80 (81.6%). Proportion of DAYCASE increased form 12% prior to 2013 to 67% in 2016. INPATIENTs were older (median 66 vs. 60 years), and had a higher proportion of PEHR (55 vs. 34%), p < 0.05. Both cohorts were comparable in gender proportion, ASA classification, and length of surgery. Complications, readmission, and emergency visits did not differ between the two cohorts. On multivariate analysis, female gender (OR 37, 95% CI 1.46-936, p = 0.028), surgery beginning after noon (OR 5.4, 95% CI 1.1-26.9, p = 0.038), intraoperative complications (OR 20.4 95% CI 1.5-286, p = 0.025), and postoperative complications (OR 52.1, 95% CI 4.5-602, p = 0.002) were independently associated with unplanned admission. CONCLUSIONS: Day-case surgery for complex laparoscopic hiatal procedures is feasible and can be achieved in a significant number of patients without compromising safety.

Gastrectomy with Extended Lymphadenectomy: a North American Perspective.

PURPOSE: Despite evidence of oncologic benefits from extended (D2) lymphadenectomy in gastric cancer from many East Asian studies, there is persistent debate over its use in the West, mainly due to perceived high rates of morbidity and mortality. This study evaluates the safety and efficacy of D2 dissection in a high-volume North American center. METHODS: A prospectively entered database of all patients undergoing gastrectomy for cancer at a North American referral center from 2005 to 2016 was reviewed. Wedge resections, thoracoabdominal approach, emergency surgery, palliative operations, and non-adenocarcinoma cases were excluded. RESULTS: Of 366 non-bariatric gastrectomies over this period, 175 met the inclusion criteria. Median age was 73 years and 69% were male. One hundred forty-one patients (80%) underwent D2 dissection, the rest having D1. There was no difference in postoperative complications (D1 = 44%: D2 = 42%), anastomotic leaks (D1 = 6%: D2 = 5%), and same-admission or 30-day mortality (D1 = 6%: D2 = 2%). D2 dissection was associated with higher pathological stage (72% > stage 1 vs 38% > stage 1; p < 0.05) and median lymph node yield (30 vs 14; p < 0.05), with no difference in complete resection (R0) rate (D1 = 98% vs D2 = 92%). Laparoscopic approach was employed in 34% (45/141) of D2 cases, resulting in shorter median length of stay (6 days vs 9; p < 0.05) and equivalent oncologic outcomes compared to open D2. CONCLUSION: This study supports the use of D2 lymphadenectomy, by either open or laparoscopic approach, in high-volume North American centers as a safe and effective oncologic procedure for gastric cancer, with equivalent complication rates and superior lymph node yield to traditional D1 dissection.

Anchoring plant metallothioneins to the inner face of the plasma membrane of Saccharomyces cerevisiae cells leads to heavy metal accumulation.

In this study we engineered yeast cells armed for heavy metal accumulation by targeting plant metallothioneins to the inner face of the yeast plasma membrane. Metallothioneins (MTs) are cysteine-rich proteins involved in the buffering of excess metal ions, especially Cu(I), Zn(II) or Cd(II). The cDNAs of seven Arabidopsis thaliana MTs (AtMT1a, AtMT1c, AtMT2a, AtMT2b, AtMT3, AtMT4a and AtMT4b) and four Noccaea caerulescens MTs (NcMT1, NcMT2a, NcMT2b and NcMT3) were each translationally fused to the C-terminus of a myristoylation green fluorescent protein variant (myrGFP) and expressed in Saccharomyces cerevisiae cells. The myrGFP cassette introduced a yeast myristoylation sequence which allowed directional targeting to the cytosolic face of the plasma membrane along with direct monitoring of the intracellular localization of the recombinant protein by fluorescence microscopy. The yeast strains expressing plant MTs were investigated against an array of heavy metals in order to identify strains which exhibit the (hyper)accumulation phenotype without developing toxicity symptoms. Among the transgenic strains which could accumulate Cu(II), Zn(II) or Cd(II), but also non-canonical metal ions, such as Co(II), Mn(II) or Ni(II), myrGFP-NcMT3 qualified as the best candidate for bioremediation applications, thanks to the robust growth accompanied by significant accumulative capacity.

Calcium signaling mediates the response to cadmium toxicity in Saccharomyces cerevisiae cells.

The involvement of Ca(2+) in the response to high Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), and Hg(2+) was investigated in Saccharomyces cerevisiae. The yeast cells responded through a sharp increase in cytosolic Ca(2+) when exposed to Cd(2+), and to a lesser extent to Cu(2+), but not to Mn(2+), Co(2+), Ni(2+), Zn(2+), or Hg(2+). The response to high Cd(2+) depended mainly on external Ca(2+) (transported through the Cch1p/Mid1p channel) but also on vacuolar Ca(2+) (released into the cytosol through the Yvc1p channel). The adaptation to high Cd(2+) was influenced by perturbations in Ca(2+) homeostasis. Thus, the tolerance to Cd(2+) often correlated with sharp Cd(2+)-induced cytosolic Ca(2+) pulses, while the Cd(2+) sensitivity was accompanied by the incapacity to rapidly restore the low cytosolic Ca(2+).

Vaccinium corymbosum L. (blueberry) extracts exhibit protective action against cadmium toxicity in Saccharomyces cerevisiae cells.

Blueberries (Vaccinium corymbosum L.) are a rich source of antioxidants and their consumption is believed to contribute to food-related protection against oxidative stress. In the present study, the chemoprotective action of blueberry extracts against cadmium toxicity was investigated using a cadmium-hypersensitive strain of Saccharomyces cerevisiae. Four varieties of blueberries were used in the study, and it was found that the extracts with high content of total anthocyanidins exhibited significant protective effect against the toxicity of cadmium and H2O2. Both the blueberry extracts and pure cyanidin exhibited protective effects against cadmium in a dose-dependent manner, but without significantly interfering with the cadmium accumulation by the yeast cells. The results imply that the blueberry extracts might be a potentially valuable food supplement for individuals exposed to high cadmium.

Point-of-care urine tests for smoking status and isoniazid treatment monitoring in adult patients.

BACKGROUND: Poor adherence to isoniazid (INH) preventive therapy (IPT) is an impediment to effective control of latent tuberculosis (TB) infection. TB patients who smoke are at higher risk of latent TB infection, active disease, and TB mortality, and may have lower adherence to their TB medications. The objective of our study was to validate IsoScreen and SmokeScreen (GFC Diagnostics, UK), two point-of-care tests for monitoring INH intake and determining smoking status. The tests could be used together in the same individual to help identify patients with a high-risk profile and provide a tailored treatment plan that includes medication management, adherence interventions, and smoking cessation programs. METHODOLOGY/PRINCIPAL FINDINGS: 200 adult outpatients attending the TB and/or the smoking cessation clinic were recruited at the Montreal Chest Institute. Sensitivity and specificity were measured for each test against the corresponding composite reference standard. Test reliability was measured using kappa statistic for intra-rater and inter-rater agreement. Univariate and multivariate logistic regression models were used to explore possible covariates that might be related to false-positive and false-negative test results. IsoScreen had a sensitivity of 93.2% (95% confidence interval [CI] 80.3, 98.2) and specificity of 98.7% (94.8, 99.8). IsoScreen had intra-rater agreement (kappa) of 0.75 (0.48, 0.94) and inter-rater agreement of 0.61 (0.27, 0.90). SmokeScreen had a sensitivity of 69.2% (56.4, 79.8), specificity of 81.6% (73.0, 88.0), intra-rater agreement of 0.77 (0.56, 0.94), and inter-rater agreement of 0.66 (0.42, 0.88). False-positive SmokeScreen tests were strongly associated with INH treatment. CONCLUSIONS: IsoScreen had high validity and reliability, whereas SmokeScreen had modest validity and reliability. SmokeScreen tests did not perform well in a population receiving INH due to the association between INH treatment and false-positive SmokeScreen test results. Development of the next generation SmokeScreen assay should account for this potential interference.