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High-intensity alkylator-based chemotherapy is required to eradicate tumors expressing high levels of O6-methylguanine DNA methyltransferase (MGMT). This treatment, however, can lead to life-threatening myelosuppression. We investigated a gene therapy strategy to protect human granulocyte colony-stimulating factor-mobilized peripheral blood CD34+ cells (MPB) from a high-intensity alkylator-based regimen. We transduced MPB with an oncoretroviral vector that coexpresses MGMTP140K and the enhanced green fluorescent protein (EGFP) (n = 5 donors). At 4 weeks posttransplantation into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, cohorts were not treated or were treated with low- or high-intensity alkylating chemotherapy. In the high-intensity-treated cohort, it was necessary to infuse NOD/SCID bone marrow (BM) to alleviate hematopoietic toxicity. At 8 weeks posttreatment, human CD45+ cells in the BM of mice treated with either regimen were EGFP+ and contained MGMT-specific DNA repair activity. In cohorts receiving low-intensity therapy, both primitive and mature hematopoietic cells were present in the BM. Although B-lymphoid and myeloid cells were resistant to in vivo drug treatment in cohorts that received high-intensity therapy, no human CD34+ cells or B-cell precursors were detected. These data suggest that improved strategies to optimize repair of DNA damage in primitive human hematopoietic cells are needed when using high-intensity anti-cancer therapy.Molecular Therapy (2006) 13, 1016–1026; doi: 10.1016/j.ymthe.2005.11.017 [ABSTRACT FROM AUTHOR]

Background: Multidrug-resistant (MDR) tuberculosis has increased among migrants in Canada. The cause(s) of this increase is unknown.Methods: We performed a retrospective cohort study in a Canadian province with substantially increased immigration between 1982-2001 and 2002-2019. The proportion of MDR tuberculosis among migrants arriving from high MDR (HMDR) tuberculosis burden countries during these 2 periods was used to estimate the proportion of cases due to immigration versus change in proportion in the country of birth. Epidemiologic, spatiotemporal, and drug resistance pattern data were used to confirm local transmission.Results: Fifty-two of 3514 (1.48%) foreign-born culture-positive tuberculosis patients had MDR tuberculosis: 8 (0.6%) in 1982-2001 and 44 (2.0%) in 2002-2019. Between time periods, the proportion of MDR tuberculosis among migrants with tuberculosis from HMDR tuberculosis countries increased from 1.11% to 3.62%, P = .003; 31.6% attributable to recent immigration and 68.4% to a higher proportion of MDR tuberculosis in cases arrived from HMDR tuberculosis countries. No cases of MDR tuberculosis were attributable to local transmission.Conclusions: In stark contrast to HMDR tuberculosis countries, local transmission plays no important role in the occurrence of MDR tuberculosis in Canada. Improved tuberculosis programming in HMDR tuberculosis countries is urgently needed. [ABSTRACT FROM AUTHOR]

Theta-shaped specimens were additively manufactured out of Inconel 718 powders using an electron beam melting technique, as a model complex load bearing structure. Two different build strategies were employed; producing two sets of specimens. Microstructural and micro-mechanical characterizations were performed using electron back-scatter, synchrotron x-ray and in-situ neutron diffraction techniques. In particular, the cross-members of the specimens were the focus of the synchrotron x-ray and in-situ neutron diffraction measurements. The build strategies employed resulted in the formation of distinct microstructures and crystallographic textures, signifying the importance of build-parameter manipulation for microstructural optimization. Large strain anisotropy of the different lattice planes was observed during in-situ loading. Texture was concluded to have a distinct effect upon both the axial and transverse strain responses of the cross-members. In particular, the (200), (220) and (420) transverse lattice strains all showed unexpected overlapping trends in both builds. This was related to the strong {200} textures along the build/loading direction, providing agreement between the experimental and calculated results. [ABSTRACT FROM AUTHOR]

The article reports on the effectiveness of notification to identify patients with human immunodeficiency virus (HIV) infections in Canada. Topics covered include the estimated population of people with such infections in the country in 2011. Also mentioned is the proportion of people unaware of their conditions.

Here we describe a blood-cleansing device for sepsis therapy inspired by the spleen, which can continuously remove pathogens and toxins from blood without first identifying the infectious agent. Blood flowing from an infected individual is mixed with magnetic nanobeads coated with an engineered human opsonin-mannose-binding lectin (MBL)-that captures a broad range of pathogens and toxins without activating complement factors or coagulation. Magnets pull the opsonin-bound pathogens and toxins from the blood; the cleansed blood is then returned back to the individual. The biospleen efficiently removes multiple Gram-negative and Gram-positive bacteria, fungi and endotoxins from whole human blood flowing through a single biospleen unit at up to 1.25 liters per h in vitro. In rats infected with Staphylococcus aureus or Escherichia coli, the biospleen cleared >90% of bacteria from blood, reduced pathogen and immune cell infiltration in multiple organs and decreased inflammatory cytokine levels. In a model of endotoxemic shock, the biospleen increased survival rates after a 5-h treatment. [ABSTRACT FROM AUTHOR]

Background: The Arab Teens Lifestyle (ATLS) questionnaire was an initiative to assess the lifestyle habits influencing obesity rates in the Middle East and North Africa (MENA) region, including physical activity (PA) patterns, sedentary and eating behaviours. Since its implementation, the ATLS questionnaire has been used in several studies among different age groups and populations. This instrument has not previously been administered among the university students of the Eastern Province of Saudi Arabia, where the obesity rates are the highest in the country. This research was the first that aimed to identify lifestyle habits influencing the rates of obesity among 18-25-year-old university students in the Eastern Province of the Kingdom of Saudi Arabia (KSA) using the ATLS questionnaire., Methods: Quantitative cross-sectional research among n = 426 students of the Eastern Province of Saudi Arabia using the ATLS questionnaire., Results: Out of n = 426 participants, n = 200 (47%) were categorised (using body mass index) as normal weight; n = 113 (26.5%) were overweight, and n = 73 (17.1%) were obese. The findings showed that most of the nutritional, PA, and sedentary behavioural factors (e.g., screen time) in the questionnaire were not associated with obesity status amongst the participants. In the obese group, more of the males that consumed fruits, French fries, cakes, sweets and doughnuts more than three times per week were likely to be obese, which was not the case for females., Conclusion: The reported lifestyles of the students could potentially lead to long-term negative health effects, which is of concern given the rising rates of overweight, obesity, and obesity-related non-communicable diseases (NCDs) among the Kingdom's adult and ageing population. Further studies are recommended to explore the knowledge, attitudes, and perceptions of Saudi students in the Eastern Province in relation to PA, sedentary behaviours, and dietary habits, along with their views on how these can be improved., (© 2024. The Author(s).)

Epidemiologic research on zoonotic tuberculosis historically used Mycobacterium bovis as a surrogate measure, however, increased reports of human tuberculosis caused by other animal-associated Mycobacterium tuberculosis complex members like Mycobacterium orygis necessitates their inclusion. We performed a retrospective cohort study including persons infected with any animal-lineage M. tuberculosis complex species in Alberta, Canada, from January 1995 to July 2021, identifying 42 patients (20 M. bovis, 21 M. orygis, one M. caprae). Demographic, epidemiologic and clinical characteristics were compared against persons with culture-confirmed M. tuberculosis infection. The proportion of culture-positive infections caused by M. orygis increased continuously from 2016-2020. Significantly more females at a higher median age were impacted by M. orygis, with all patients originating from South Asia. M. bovis caused significantly more extra-pulmonary disease, and disproportionately impacted young females, particularly those pregnant or post-partum. All infections were acquired abroad. These findings can aid in developing targeted public health interventions., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Next-generation sequencing (NGS) is essential to the care of patients with NSCLC. Nevertheless, NGS is dependent on adequate material from biopsy. We evaluated the impact of biopsy method and needle gauge necessary for optimizing success in tissue NGS., Methods: A total of 1660 formalin-fixed, paraffin-embedded samples were submitted to Caris Life Sciences from 2007 to 2022 for tumor profiling. The results of NGS assays were linked with retrospective biopsy data for patients with lung cancer treated at USC/Norris Cancer Center to create a database with the following parameters: demographics, biopsy method, tumor location (lung mass versus lymph node versus metastasis), needle gauge, number of needle passes, complications, tumor volume, DNA content, and status of NGS. Fisher's exact test and analysis of variance were performed to determine the impact of biopsy method and needle gauge (G)., Results: In total, 77 computed tomography (CT)-guided transthoracic core needle (CT-TTCN) biopsies, 74 endobronchial ultrasound (EBUS)-guided transbronchial needle aspirations (TBNAs), 27 bronchial forceps biopsies, and 107 surgical resections were included. Furthermore, 41 of 77 CT-TTCN biopsies (53.2%), 43 of 74 EBUS-TBNAs (58.1%), 22 of 27 bronchial forceps biopsies (81.5%), and 105 of 107 surgical resections (98.1%) underwent successful NGS assays. The probability of successful NGS completion for lung cancers was highest in surgical resections and bronchial forceps biopsies. Needle-based biopsies were more successful when a needle larger than 20G was used. Complication rates were higher for CT-TTCN biopsies compared with EBUS-TBNA ( p < 0.0001). Overall, the DNA yield was significantly higher in EBUS-TBNA compared with CT-TTCN biopsies in primary lung sites ( p  = 0.0002). EBUS-TBNA was found to have higher success rates in NGS compared with CT-TTCN for both primary lung lesions ( p  = 0.023) and lymph node targets ( p  = 0.035)., Conclusions: The less invasive EBUS-TBNAs had higher success rates in NGS than CT-TTCN biopsies and resulted in higher DNA concentrations. In CT-TTCN biopsies, use of 20G or smaller needles is associated with a higher risk of obtaining an inadequate specimen regardless of the number of passes taken. Surgical and bronchial forceps biopsies had highest success in achieving NGS., (© 2023 The Authors.)

Background: Inclusion and exclusion criteria in clinical trials are used to mitigate the effects of confounding variables on study outcomes. In 2017 and 2021, ASCO and the Friends of Cancer Research published recommendations to loosen enrollment criteria in cancer clinical trials to improve generalizability. The purpose of this study is to determine if the source of funding influences the degree of transparency and selection of inclusion and exclusion criteria., Methods: Phase 2 and 3 non-small cell lung cancer (NSCLC) drug trials on clinicaltrials.gov were grouped into one of three sponsor categories: industry, government/cooperative group, and academic. Strictness of specific criteria and the level of transparency in listing organ function requirements were analyzed using Fisher Exact tests. Independent sample t-tests were used to assess the variability in total number of criteria., Results: Organ function requirements listed on clinicaltrials.gov are more often vague or incomplete in industry sponsored trials compared to government/cooperative group (p = 2.3 × 10 -10 , α = 0.01) and academic (p = 1.8 × 10 -4 , α = 0.01) sponsored trials. Industry sponsored trials more often excluded patients with worse performance status scores compared to government/cooperative group sponsored trials (p = 5.7 × 10 -6 , α = 0.01)., Conclusion: Industry sponsored NSCLC drug trials are more likely to exclude patients with worse performance status and are less transparent in listing complete study requirements on clinicaltrials.gov., Policy Summary: Unnecessarily strict enrollment criteria are increasingly seen in clinical trials sponsored by industry. Regulators responsible for drug approvals should note when studies deviate from ASCO and Friends of Cancer Research framework and question the external validity of study findings with overly narrow enrollment criteria when making decisions on drug approvals., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The last decade has seen a dramatic shift toward the study of fitness surveillance, thanks in part to the emergence of mobile health (mHealth) apps that allow users to track their health through a variety of data-driven insights. This study examines the adoption trends and community mediation of the mobile fitness application 'FanFit', a platform aimed at promoting physical activity among sports fans by creating a fitness app branded to their favourite team for health promotion. Objective: Our study looked at the impact of a specially designed mobile app (FanFit) as a digital health intervention for initiating and maintaining physical activity as part of football club membership. Our analysis indicates that app users will adopt healthier behaviours as a result of the app's sense of fan community and behaviour change. Methods: The findings reported here are based on an implementation of the FanFit app and, in particular, on those who participated in a more in-depth study ( n = 30). These participants were Rangers FC supporters with a mix of genders (n = 19 males and n = 11 females). Focus groups and interviews were conducted with participants to ascertain users' perspectives on the most effective methods for nudging users toward adopting and maintaining a pattern of fitness behaviours. Results: The findings show that the user community was interested in fitness and wanted to live a 'healthy lifestyle,' which was augmented and fuelled by the app's competitive architecture design. Furthermore, the data reveal a new fan-health discourse about a person's developing wants, talents, and identities as embodied beings. Conclusions: We have developed and presented valid links between the use of sports club apps and health programmes. The app could be useful for sports programmes and club providers looking for mHealth applications that provide community support through fan discourse with opportunities for both male and female fans.

Objectives: We propose a new topical radiographic contrast method for distinguishing noncavitated from cavitated radiolucencies. Laboratory tests and a pilot clinical trial were designed to test the feasibility and efficacy of the method., Study Design: Twenty-two adults with 27 proximal radiolucencies had conventional bitewing (BW) examinations. After exclusion, 21 surfaces were evaluated. A concentrated solution of sodium iodide was placed in the interdental spaces via a microsyringe and BWs were again exposed. A class II cavity preparation was made in the adjacent tooth and polysiloxane impressions were made of the study surfaces. The impressions were scanned by visible light, creating a high resolution 3D replica. Cavitations, if present, were measured., Results: Nine surfaces were noncavitated and 12 surfaces were cavitated. The microsyringe dispensed a variable volume of liquid, which affected the accuracy of the test. The sensitivity for cavitation was 50%, specificity was 88.9%, and accuracy was 66.7%. This compares to a reported 60% sensitivity, 62% specificity, and 62% accuracy for BW examinations. Intraexaminer reliability for classifying noncavitated or cavitated lesions using the kappa test was 0.649., Conclusions: This method needs improvement but was an advance over conventional BWs and could result in reduction of restorations in low- and high-risk patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Human alveolar echinococcosis (AE) is a zoonotic cestode infection which is usually fatal in the absence of treatment. Treatment involves major surgery or indefinite antiparasitic therapy. The incidence is rising in Europe and Asia, with an increased risk observed in immunocompromised individuals. Previously, AE acquisition in North America was extremely rare, except for one remote Alaskan Island. Recent studies have demonstrated a new European-like strain of Echinococcus multilocularis (Em) in wildlife and in human AE in western Canada. We report the experience of all AE patients diagnosed in Alberta. Each was diagnosed by histopathology, serology, and PCR-confirmed by a reference laboratory. Seventeen cases of human AE, aged 19-78 years, nine females, were diagnosed between 2013 and 2020: all definitely or probably acquired in Alberta. Six lived in urban areas, and 14 had kept dogs. In eight, the lesions were found incidentally on abdominal imaging performed for other indications. Six were immunocompromised to varying degrees. Six were first diagnosed at surgery. All have been recommended benzimidazole therapy. One died of surgical complications. Clinicians should be aware of this diagnostic possibility in patients presenting with focal nonmalignant hepatic mass lesions. Greater urbanization of coyotes, the predominant definitive host of Em in Alberta, and growing numbers of immune suppressed individuals in the human population may lead to increasing recognition of AE in North America.

Aims: E-cigarettes have been advocated as an effective smoking cessation intervention, with evidence indicating that they are substantially less harmful than conventional cigarettes. As a result, a pilot to encourage people to swap from conventional cigarettes to e-cigarettes was conducted in 2018 in a socially deprived area in the North West of England. This evaluation highlights the key findings from the pilot., Methods: An analysis of secondary data at 4 weeks ( n = 1022) was undertaken to predict those who used solely used e-cigarettes (i.e. had quit tobacco, as confirmed by a carbon monoxide test, CO < 10 ppm) from baseline characteristics, using chi-square tests and logistic regression. Baseline data were demographics, smoking levels and service provider type., Results: Of the 1022 participants who engaged with the pilot 614 were still engaged at 4 weeks, of whom 62% had quit; quitting was more likely in younger participants (aged 18-24) and less likely in those who were sick and disabled. Of those who still smoked tobacco at week 4 ( n = 226), smoking had reduced from a baseline of 19.1 cigarettes/day to 8.7. Overall, 37% (381) of those initially enrolled were confirmed to be using an e-cigarette on its own at follow-up. Successful quit was associated with occupation (unemployed, 33% vs intermediate, 47%, p = .023) and residing in the less deprived quintiles of deprivation (50% vs 34% in the most deprived quintile, p = .016)., Conclusions: Making the conservative assumption that all those not in contact at 4 weeks were still smoking tobacco, for every five people entering the scheme, three people stayed on the programme and reduced their cigarette smoking and one person cut out tobacco altogether. E-cigarettes appear to be an effective nicotine replacement therapy; however, further research is required to determine whether e-cigarette users are more likely to reduce their overall nicotine consumption in the longer term.

Objectives: Canada has accepted more than 25,000 Syrian refugees fearing persecution in their homeland. Canadian guidelines recommend screening recent refugees from high incidence countries for tuberculosis (TB) and latent TB infection (LTBI). The prevalence of TB in this population is unknown. A refugee clinic in Edmonton presented a unique opportunity to estimate prevalence of TB and LTBI in Syrian refugees arriving in Canada., Methods: In January 2016, 100 consecutive Syrian refugees were screened for TB with clinical assessment and LTBI using QuantiFERON Gold In-Tube assay (QFT-GIT). Patients with positive QFT-GIT were referred to Edmonton Tuberculosis Clinic (ETBC) for evaluation and, if appropriate, offered prophylaxis., Results: No cases of active TB were found. Valid QFT-GIT were measured in 99 of 100 individuals and of these, nine (9%) were positive using a threshold concentration of blood interferon-γ greater than 0.35 IU/L. Eight of the nine patients attended follow-up appointments; of these, seven began LTBI prophylaxis and all seven (78%) completed same., Conclusion: The 9% (95% confidence interval 3-15%) prevalence of LTBI was higher than expected in this population.

Lead (Pb) produces aggresome-like inclusion bodies (IBs) in target cells as a toxic response. Our prior work shows metallothionein (MT) is required for this process. We used MT-I/II double knockout (MT-null) and parental wild-type (WT) cell lines to further explore the formation process of Pb-induced IBs. Unlike WT cells, MT-null cells did not form IBs after Pb exposure. Western blot of cytosol showed soluble MT protein in WT cells was lost during Pb exposure as IBs formed. Transfection of MT-I into MT-null cells allowed IBs formation after Pb exposure. Considering Pb-induced IBs may be like disease-related aggresomes, which often contain alpha-synuclein (Scna), we investigated Scna expression in cells capable (WT) and incapable (MT-null) of producing IBs after Pb exposure. Scna protein showed poor basal expression in MT-null cells. Pb exposure increased Scna expression only in WT cells. MT transfection increased Scna transcript to WT levels. In WT or MT-transfected MT-null cells, Pb-induced Scna expression rapidly increased and then decreased over 48 h as Pb-induced IBs were formed. A direct interaction between Scna and MT was confirmed ex vivo by antibody pulldown assay where the proteins coprecipitated with an antibody to MT. Pb exposure caused increased colocalization of MT and Scna proteins with time only in WT cells. In WT mice after chronic Pb exposure Scna was localized in renal cells containing forming IBs, whereas MT-null mice did not form IBs. Thus, Scna could be component of Pb-induced IBs and, with MT, may play a role in IBs formation.

We report fluctuations in resistivity and the manifestation of Coulomb blockade phenomena of conductive multiwalled carbon nanotubes under buckling loads. Individual nanotubes were suspended and soldered between two indium-dipped tungsten probe tips. Using the electrical connection between the probes and the nanotube, electrical measurements were taken with the tube straight (unstrained) and bent (strained). Typical resistances were in the 10 G Omega range with resistivities in the 15 to 30 Omega-m range within the Coulomb blockade region of -1.0 to -0.4 V. Coulomb blockade, or electron tunneling events, appeared to occur at one of the contact points. This effect was diminished or lost once the carbon weld was broken.

DNA repair capacity of eukaryotic cells has been studied extensively in recent years. Mammalian cells have been engineered to overexpress recombinant nuclear DNA repair proteins from ectopic genes to assess the impact of increased DNA repair capacity on genome stability. This approach has been used in this study to specifically target O(6)-methylguanine DNA methyltransferase (MGMT) to the mitochondria and examine its impact on cell survival after exposure to DNA alkylating agents. Survival of human hematopoietic cell lines and primary hematopoietic CD34(+) committed progenitor cells was monitored because the baseline repair capacity for alkylation-induced DNA damage is typically low due to insufficient expression of MGMT. Increased DNA repair capacity was observed when K562 cells were transfected with nuclear-targeted MGMT (nucl-MGMT) or mitochondrial-targeted MGMT (mito-MGMT). Furthermore, overexpression of mito-MGMT provided greater resistance to cell killing by 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) than overexpression of nucl-MGMT. Simultaneous overexpression of mito-MGMT and nucl-MGMT did not enhance the resistance provided by mito-MGMT alone. Overexpression of either mito-MGMT or nucl-MGMT also conferred a similar level of resistance to methyl methanesulfonate (MMS) and temozolomide (TMZ) but simultaneous overexpression in both cellular compartments was neither additive nor synergistic. When human CD34(+) cells were infected with oncoretroviral vectors that targeted O(6)-benzylguanine (6BG)-resistant MGMT (MGMT(P140K)) to the nucleus or the mitochondria, committed progenitors derived from infected cells were resistant to 6BG/BCNU or 6BG/TMZ. These studies indicate that mitochondrial or nuclear targeting of MGMT protects hematopoietic cells against cell killing by BCNU, TMZ, and MMS, which is consistent with the possibility that mitochondrial DNA damage and nuclear DNA damage contribute equally to alkylating agent-induced cell killing during chemotherapy.