The Challenge of Reaching Undocumented Migrants with COVID-19 Vaccination.

Access to vaccination against a health threat such as that presented by the COVID-19 pandemic is an imperative driven, in principle, by at least three compelling factors: (1) the right to health of all people, irrespective of their status; (2) humanitarian need of undocumented migrants, as well as of others including documented migrants, refugees and displaced people who are sometimes vulnerable and living in precarious situations; and (3) the need to ensure heath security globally and nationally, which in the case of a global pandemic requires operating on the basis that, for vaccination strategies to succeed in fighting a pandemic, the highest possible levels of vaccine uptake are required. Yet some population segments have had limited access to mainstream health systems, both prior to as well as during the COVID-19 pandemic. People with irregular resident status are among those who face extremely high barriers in accessing both preventative and curative health care. This is due to a range of factors that drive exclusion, both on the supply side (e.g., systemic and practical restrictions in service delivery) and the demand side (e.g., in uptake, including due to fears that personal data would be transmitted to immigration authorities). Moreover, undocumented people have often been at increased risk of infection due to their role as "essential workers", including those experiencing higher exposure to the SARS-CoV-2 virus due to frontline occupations while lacking protective equipment. Often, they have also been largely left out of social protection measures granted by governments to their populations during successive lockdowns. This article reviews the factors that serve as supply-side and demand-side barriers to vaccination for undocumented migrants and considers what steps need to be taken to ensure that inclusive approaches operate in practice.

Increasing socioeconomic disparities in tobacco smoking decline among French adolescents (2000-2017).

BACKGROUND: This paper studies the evolution of transitions from first cigarette use to daily use by socioeconomic status (SES) among French adolescents over the course of 17 years, in a context of decreasing prevalence of tobacco use. METHODS: A total of 182 266 adolescents participated in the nationally representative ESCAPAD survey at nine different time points between 2000 and 2017. Discrete time-event analysis was used to model the transition to daily cigarette use as a function of SES, gender, age at onset and the use of other psychoactive substances. RESULTS: Although lifetime cigarette smoking and daily cigarette smoking decreased significantly over the studied time span, suggesting a positive impact of prevention policies, disadvantaged adolescents were consistently more prone to engage in daily cigarette smoking, more so in 2017 than 15 years earlier. In the same time span, transitions from initiation to daily cigarette smoking have shortened, with an accelerated pace among underprivileged adolescents. CONCLUSIONS: Accelerated transitions from initiation to daily cigarette use are a prevalent trend among disadvantaged adolescents in France. Efforts to mitigate the impact of marketing strategies and to promote health literacy should be pursued to reduce social inequalities in health.

Doping among high school students: findings from the French ESPAD survey.

BACKGROUND: The increasing use of doping by youth is a growing public health concern. The present study aimed to calculate robust estimates of the prevalence of doping among French high school students and study factors related to the use of licit vs. banned agents. METHODS: The European School Project on Alcohol and other Drugs (ESPAD), a nationally representative school-based survey, was distributed across France from April to May 2015, generating a final sample size of 6642 students. Multilevel modelling was used to examine covariates of doping to enhance athletic performance in sport in this population. RESULTS: Overall, 2.3% of students used banned agents, and 6.1% used licit and banned substances to improve athletic performance. Significant gender differences existed for both, with males more prone to doping than females. Our findings provide support for the existing gateway hypothesis that nutritional supplementation leads to doping banned agents. Multilevel modelling revealed the presence of both school and class-level influences on individual use of licit substances, vs. solely class-level factors impacting the use of banned agents, suggesting a strong peer-effect. CONCLUSIONS: These findings support the need to engage in early doping prevention through high schools. Programmes should draw attention to the role of licit substances, including nutritional supplementation, in the progression to using banned agents and encompass the continuum of adolescent risk taking through a behaviour-based approach to doping prevention.

Age of Initiation and Patterns of Use among People Who Inject Drugs Welcomed in Harm Reduction Facilities in France from 2006 to 2015.

This exploratory analysis of time-series cross-sectional data provides insights on trends in age at first injection among people who inject drugs in France, and on associations with recent risky injecting behaviors. Data were collected from a national survey conducted in harm reduction facilities in five phases between 2006 and 2015. Standardized questionnaires collected information on demographics, substance use, and route of administration, as well as lifetime and past-month injection. Descriptive and multilevel models were applied to account for the hierarchical structure of the data. Prevalence of lifetime and past-month injection remained stable over time, while the prevalence of daily injection increased significantly. Mean age at first injection only appeared to increase for data collected after 2010. Gender differences in mean age at first injection decreased over time, suggesting the development of converging patterns of initiation independent of sex. After controlling for covariates, early initiation of injection was unrelated to daily injection or material sharing, and associated with the number of recently injected substances. Early initiation is likely a predictor of injected polysubstance use. Findings are relevant to the planning, implementation, and evaluation of prevention programs.

On the question of non-medical cognitive enhancers among in-school adolescents: prevalence, predictors and potential health-related harms.

Little is known about the use of non-medical cognitive enhancers (NCEs) in the general population, and even less among youth. The study utilises a nationally representative, cross-sectional survey of adolescents attending high schools to provide a comprehensive overview of NCEs and to assess risk factors such as socio-demographics, schooling, mental health and related substance use among French adolescents. A total of 6692 students attending high school (secondary schools) answered an anonymous questionnaire collecting information on demographics, health, psychoactive substance uses (neuroleptics, tobacco, alcohol, cannabis, illicit substances) and patterns of sociability. The use of cognitive enhancers appears to be an underestimated phenomenon among youth. Prevalence of use is heavily gender-influenced, with females twice as likely to use NCEs than males. More than daily school commitments, the use of cognitive enhancers is related to the proximity of the national secondary education examination. Moreover, mental health, use of prescribed anxiolytics and other psychoactive substances are significantly independently associated with the use of cognitive enhancers, particularly among females. The unregulated use of cognitive enhancers is a predictor of potential mental frailty and a substance-based response to stressful events, a behaviour likely to persist during adulthood. The study underpins the lack of contextual and comparable data. Systematic monitoring of younger students in neighbouring countries is required to develop reliable prevention programmes.

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates ß-Catenin Signaling and Tumorigenesis in Multiple Cancer Types.

Deregulation of the ß-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and ß-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate ß-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate ß-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, gene-expression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited ß-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of ß-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis.

Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency.

PURPOSE: The Notch pathway plays an important role in both stem cell biology and cancer. Dysregulation of Notch signaling has been reported in several human tumor types. In this report, we describe the development of an antibody, OMP-59R5 (tarextumab), which blocks both Notch2 and Notch3 signaling. EXPERIMENTAL DESIGN: We utilized patient-derived xenograft tumors to evaluate antitumor effect of OMP-59R5. Immunohistochemistry, RNA microarray, real-time PCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts. RESULTS: We found that anti-Notch2/3, either as a single agent or in combination with chemotherapeutic agents was efficacious in a broad spectrum of epithelial tumors, including breast, lung, ovarian, and pancreatic cancers. Notably, the sensitivity of anti-Notch2/3 in combination with gemcitabine in pancreatic tumors was associated with higher levels of Notch3 gene expression. The antitumor effect of anti-Notch2/3 in combination with gemcitabine plus nab-paclitaxel was greater than the combination effect with gemcitabine alone. OMP-59R5 inhibits both human and mouse Notch2 and Notch3 function and its antitumor activity was characterized by a dual mechanism of action in both tumor and stromal/vascular cells in xenograft experiments. In tumor cells, anti-Notch2/3 inhibited expression of Notch target genes and reduced tumor-initiating cell frequency. In the tumor stroma, OMP-59R5 consistently inhibited the expression of Notch3, HeyL, and Rgs5, characteristic of affecting pericyte function in tumor vasculature. CONCLUSIONS: These findings indicate that blockade of Notch2/3 signaling with this cross-reactive antagonist antibody may be an effective strategy for treatment of a variety of tumor types.

Identification of CBX3 and ABCA5 as putative biomarkers for tumor stem cells in osteosarcoma.

Recently, there has been renewed interest in the role of tumor stem cells (TSCs) in tumorigenesis, chemoresistance, and relapse of malignant tumors including osteosarcoma. The potential exists to improve osteosarcoma treatment through characterization of TSCs and identification of therapeutic targets. Using transcriptome, proteome, immunophenotyping for cell-surface markers, and bioinformatic analyses, heterogeneous expression of previously reported TSC or osteosarcoma markers, such as CD133, nestin, POU5F1 (OCT3/4), NANOG, SOX2, and aldehyde dehydrogenase, among others, was observed in vitro. However, consistently significantly lower CD326, CD24, CD44, and higher ABCG2 expression in TSC-enriched as compared with un-enriched osteosarcoma cultures was observed. In addition, consistently higher CBX3 expression in TSC-enriched osteosarcoma cultures was identified. ABCA5 was identified as a putative biomarker of TSCs and/or osteosarcoma. Lastly, in a high-throughput screen we identified epigenetic (5-azacytidine), anti-microtubule (vincristine), and anti-telomerase (3,11-difluoro-6,8,13-trimethyl- 8H-quino [4,3,2-kl] acridinium methosulfate; RHPS4)-targeted therapeutic agents as candidates for TSC ablation in osteosarcoma.

Comprehensive perinatal safety initiative to reduce adverse obstetric events.

A comprehensive perinatal safety initiative (PSI) was incrementally introduced from August 2007 to July 2009 at a large tertiary medical center to reduce adverse obstetrical outcomes. The PSI introduced: (1) evidence-based protocols, (2) formalized team training with emphasis on communication, (3) standardization of electronic fetal monitoring with required documentation of competence, (4) a high-risk obstetrical emergency simulation program, and (5) dissemination of an integrated educational program among all healthcare providers. Eleven adverse outcome measures were followed prospectively via modification of the Adverse Outcome Index (MAOI). Additionally, individual components were evaluated. The logistic regression model found that within the first year, the MAOI decreased significantly to 0.8% from 2% (p<.0004) and was maintained throughout the 2-year period. Significant decreases over time for rates of return to the operating room (p<.018) and birth trauma (p<.0022) were also found. Finally, significant improvements were found in staff perceptions of safety (p<.0001), in patient perceptions of whether staff worked together (p<.028), in the management (p<.002), and documentation (p<.0001) of abnormal fetal heart rate tracings, and the documentation of obstetric hemorrhage (p<.019). This study demonstrates that a comprehensive PSI can significantly reduce adverse obstetric outcomes, thereby improving patient safety and enhancing staff and patient experiences.