Trends in educational inequalities in smoking-attributable mortality and their impact on changes in general mortality inequalities: evidence from England and Wales, Finland, and Italy (Turin).

BACKGROUND: Socioeconomic mortality inequalities are persistent in Europe but have been changing over time. Smoking is a known contributor to inequality levels, but knowledge about its impact on time trends in inequalities is sparse. METHODS: We studied trends in educational inequalities in smoking-attributable mortality (SAM) and assessed their impact on general mortality inequality trends in England and Wales (E&W), Finland, and Italy (Turin) from 1972 to 2017. We used yearly individually linked all-cause and lung cancer mortality data by educational level and sex for individuals aged 30 and older. SAM was indirectly estimated using the Preston-Glei-Wilmoth method. We calculated the slope index of inequality (SII) and performed segmented regression on SIIs for all-cause, smoking and non-SAM to identify phases in inequality trends. The impact of SAM on all-cause mortality inequality trends was estimated by comparing changes in SII for all-cause with non-SAM. RESULTS: Inequalities in SAM generally declined among males and increased among females, except in Italy. Among males in E&W and Finland, SAM contributed 93% and 76% to declining absolute all-cause mortality inequalities, but this contribution varied over time. Among males in Italy, SAM drove the 1976-1992 increase in all-cause mortality inequalities. Among females in Finland, increasing inequalities in SAM hampered larger declines in mortality inequalities. CONCLUSION: Our findings demonstrate that differing education-specific SAM trends by country and sex result in different inequality trends, and consequent contributions of SAM on educational mortality inequalities. The following decades of the smoking epidemic could increase educational mortality inequalities among Finnish and Italian women.

Disruption of hospital care during the first year of the COVID-19 pandemic impacted socioeconomic groups differently: population based study using routine registration data.

BACKGROUND: During the COVID-19 pandemic, provision of non-COVID healthcare was recurrently severely disrupted. The objective was to determine whether disruption of non-COVID hospital use, either due to cancelled, postponed, or forgone care, during the first pandemic year of COVID-19 impacted socioeconomic groups differently compared with pre-pandemic use. METHODS: National population registry data, individually linked with data of non-COVID hospital use in the Netherlands (2017-2020). in non-institutionalised population of 25-79 years, in standardised household income deciles (1 = low, 10 = high) as proxy for socioeconomic status. Generic outcome measures included patients who received hospital care (dichotomous): outpatient contact, day treatment, inpatient clinic, and surgery. Specific procedures were included as examples of frequently performed elective and acute procedures, e.g.: elective knee/hip replacement and cataract surgery, and acute percutaneous coronary interventions (PCI). Relative risks (RR) for hospital use were reported as outcomes from generalised linear regression models (binomial) with log-link. An interaction term was included to assess whether income differences in hospital use during the pandemic deviated from pre-pandemic use. RESULTS: Hospital use rates declined in 2020 across all income groups. With baseline (2019) higher hospital use rates among lower than higher income groups, relatively stronger declines were found for lower income groups. The lowest income groups experienced a 10% larger decline in surgery received than the highest income group (RR 0.90, 95% CI 0.87 - 0.93). Patterns were similar for inpatient clinic, elective knee/hip replacement and cataract surgery. We found small or no significant income differences for outpatient clinic, day treatment, and acute PCI. CONCLUSIONS: Disruption of non-COVID hospital use in 2020 was substantial across all income groups during the acute phases of the pandemic, but relatively stronger for lower income groups than could be expected compared with pre-pandemic hospital use. Although the pandemic's impact on the health system was unprecedented, healthcare service shortages are here to stay. It is therefore pivotal to realise that lower income groups may be at risk for underuse in times of scarcity.

The contribution of Dutch municipalities to stimulate smoke-free outdoor sports clubs: a qualitative study.

Local governments may play a key role in making outdoor sports clubs smoke free. This study aims to assess the activities, motives, challenges and strategies of Dutch municipalities regarding stimulating outdoor sports clubs to become smoke free. Semi-structured interviews were conducted with 19 policy officers of different municipalities in the Netherlands. The included municipalities varied in terms of region, population size and degree of urbanization. Data were analyzed using content analysis. Municipalities stimulated sports clubs to become smoke free by providing information and support and, to a lesser extent, by using financial incentives. Motives of municipalities varied from facilitating a healthy living environment for youth, responding to denormalization of smoking and aligning with goals formulated in national prevention policy. Policy officers faced several challenges, including limited capacity and funds, a reluctance to interfere with sports clubs and little support within the municipal organization. These challenges were addressed by employing various strategies such as embedding smoke-free sports in a broader preventive policy, setting a good example by creating outdoor smoke-free areas around municipal buildings, and collaborating with stakeholders in the municipality to join forces in realizing smoke-free sports clubs. Municipalities demonstrated evident motivation to contribute to a smoke-free sports environment. Currently, most municipalities fulfil an informative and supportive role, while some municipalities still explore their role and position in relation to supporting sports clubs to become smoke free. Other municipalities have established, according to them, effective strategies.

Smoking Cessation Support in Social and Community Service Organizations: Potential Activities, Barriers, and Facilitators.

INTRODUCTION: Social and Community Service Organizations (SCSOs) are a potential setting to reach and support people with a low socioeconomic position who smoke, yet smoking cessation is not widely supported by SCSO professionals. AIMS AND METHODS: This study aims to identify SCSO professionals' (1) potential activities to support smoking cessation and (2) barriers and facilitators in undertaking these activities. Between July and November 2022, semi-structured interviews were conducted with 21 professionals recruited through SCSOs in Amsterdam North, including participation workers, welfare workers, parent and child counselors, budget coach, debt counselor, welfare work, community sports, and community center coordinators. Data were analyzed using a thematic approach. RESULTS: Eight activities were identified that could support the client either directly (ie, recognizing smoking clients, discussing smoking and smoking cessation, referring clients, providing smoking cessation counseling, offering help around services) or indirectly (ie, collaboration with relevant network partners, implementing smoke-free environments, enhancing professional skills). Various barriers and facilitators were identified related to the (1) client and their environment (ie, clients' readiness and social environment), (2) interaction between professional and client (ie, topic sensitivity), (3) professional (ie, professional is non-smoker, knowledge, and self-efficacy), (4) professionals' work environment (ie, necessity, responsibility, priority, and time), and (5) smoking cessation services (ie, availability of appropriate services and referral process). CONCLUSIONS: There is potential for SCSO professionals to support smoking cessation, but several barriers hinder their efforts. To address these barriers, it is essential to take into account the factors that SCSO professionals believe facilitate the provision of smoking cessation support. IMPLICATIONS: This study provides insight into how the potential of SCSOs in Amsterdam North to support smoking cessation efforts among people with a low socioeconomic position can be harnessed. Barriers were found at multiple levels (client, professional, client-professional interaction, and organizational) and these findings imply that stakeholders across these levels will need to prioritize smoking cessation to facilitate and stimulate SCSO professionals in supporting smoking cessation. A concrete action would be to offer SCSO professionals additional training in conversational skills to discuss smoking. As a prerequisite, easily accessible and suitable smoking cessation services should be available in the neighborhood.

Pharmaceutical Approach to Develop Novel Photosensitizer Nanoformulation: An Example of Design and Characterization Rationale of Chlorophyll α Derivative.

In this study, we described physico-chemical properties of novel nanoformulation of photosensitizer-pyropheophorbide α 17-diethylene glycol ester (XL) (chlorophyll α derivative), revealing insights into antitumor activity and maintaining quality, meeting the pharmaceutical approach of new nanoformulation design. Our formulation, based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles, increased XL solubility and selective tumor-targeted accumulation. In our research, we revealed, for the first time, that XL binding to polyvinyl alcohol (PVA) enhances XL photophysical activity, providing the rationale for PVA application as a stabilizer for nanoformulations. Results of FTIR, DSC, and XRD revealed the physical interactions between XL and excipients, including PVA, indicating that the encapsulation maintained XL binding to PVA. The encapsulated XL exhibited higher photophysical activity compared to non-encapsulated substance, which can be attributed to the influence of residual PVA. Gamma-irradiation led to degradation of XL; however, successful sterilization of the samples was achieved through the filtration. Importantly, the encapsulated and sterilized XL retained cytotoxicity against both 2D and 3D tumor cell models, demonstrating the potential of the formulated NP-XL for photodynamic therapy applications, but lacked the ability to reactivate epigenetically silenced genes. These findings provide valuable insights into the design and characterization of PLGA-based nanoparticles for the encapsulation of photosensitizers.

Outdoor smoke-free policies at sports clubs across Europe: Current status, recent evidence, and future challenges.

OBJECTIVE: This commentary emphasizes the importance of implementing outdoor smoke-free policies at sports clubs, particularly highlighting their limited adoption across Europe. The primary aim was to assess the progress made in the Netherlands, explore the strategies employed, and outline future challenges. METHODS: Our methodology involved an examination of national regulations and the voluntary adoption of smoke-free policies at sports clubs throughout Europe. We also assessed the adoption and implementation of these policies using recent evidence, leading to the identification of impending challenges in their implementation across Europe. RESULTS: While only a few European countries currently have national legislation prohibiting outdoor smoking at sports clubs, voluntary initiatives promoting such policies have emerged in various nations. Experiences from the Netherlands have demonstrated the feasibility of implementing outdoor smoke-free policies at sports clubs. To expand these policies across Europe, five key challenges need to be addressed: 1) encouraging smoke-free policies at sports clubs that are less inclined to adopt them, 2) ensuring consistent compliance and enforcement of outdoor smoke-free policies, 3) preventing smoking just outside the sports club, 4) garnering support from various stakeholders to ensure widespread adoption of smoke-free sports clubs, and 5) establishing monitoring and evaluation mechanisms for policy implementation. CONCLUSION: The Dutch experiences serve as a testimony to the feasibility of outdoor smoke-free policies at sports clubs. By addressing the remaining challenges, we can create healthier sports environments for children and take substantial steps towards realizing a smoke-free Europe.

Cooperative lipolytic control of neuronal triacylglycerol by spastic paraplegia-associated enzyme DDHD2 and ATGL.

Intracellular lipolysis-the enzymatic breakdown of lipid droplet-associated triacylglycerol (TAG)-depends on the cooperative action of several hydrolytic enzymes and regulatory proteins, together designated as lipolysome. Adipose triglyceride lipase (ATGL) acts as a major cellular TAG hydrolase and core effector of the lipolysome in many peripheral tissues. Neurons initiate lipolysis independently of ATGL via DDHD domain-containing 2 (DDHD2), a multifunctional lipid hydrolase whose dysfunction causes neuronal TAG deposition and hereditary spastic paraplegia. Whether and how DDHD2 cooperates with other lipolytic enzymes is currently unknown. In this study, we further investigated the enzymatic properties and functions of DDHD2 in neuroblastoma cells and primary neurons. We found that DDHD2 hydrolyzes multiple acylglycerols in vitro and substantially contributes to neutral lipid hydrolase activities of neuroblastoma cells and brain tissue. Substrate promiscuity of DDHD2 allowed its engagement at different steps of the lipolytic cascade: In neuroblastoma cells, DDHD2 functioned exclusively downstream of ATGL in the hydrolysis of sn-1,3-diacylglycerol (DAG) isomers but was dispensable for TAG hydrolysis and lipid droplet homeostasis. In primary cortical neurons, DDHD2 exhibited lipolytic control over both, DAG and TAG, and complemented ATGL-dependent TAG hydrolysis. We conclude that neuronal cells use noncanonical configurations of the lipolysome and engage DDHD2 as dual TAG/DAG hydrolase in cooperation with ATGL.

Uridine as a Regulator of Functional and Ultrastructural Changes in the Brain of Rats in a Model of 6-OHDA-Induced Parkinson's Disease.

Using a model of Parkinson's disease (PD) induced by the bilateral injection of neurotoxin 6-hydroxydopamine (6-OHDA) into rat brain substantia nigra (SN), we showed uridine to exert a protective effect associated with activation of the mitochondrial ATP-dependent potassium (mitoK-ATP) channel. Injection of 4 µg neurotoxin evoked a 70% decrease in the time the experimental animal spent on the rod in the RotaRod test, an increase in the amount of lipid peroxides in blood serum and cerebral-cortex mitochondria and the rate of reactive oxygen species formation, and a decrease in Ca2+ retention in mitochondria. Herewith, lymphocytes featured an increase in the activity of lactate dehydrogenase, a cytosolic enzyme of glycolysis, without changes in succinate-dehydrogenase activity. Structural changes occurring in the SN and striatum manifested themselves in the destruction of mitochondria, degeneration of neurons and synapses, and stratification of myelin sheaths in them. Subcutaneous injections of 30 µg/kg uridine for 22 days restored the neurotoxin-induced changes in these parameters to levels close to the control. 5-Hydroxydecanoate (5 mg/kg), a specific mitoK-ATP channel inhibitor, eliminated the beneficial effect of uridine for almost all characteristics tested, indicating the involvement of the mitoK-ATP channel in the protective effect of uridine. The mechanism of the protective effect of uridine and its therapeutic applications for the prevention and treatment of PD are discussed.

Socioeconomic differences in tobacco outlet presence, density, and proximity in four cities in the Netherlands.

BACKGROUND: Previous studies found that tobacco outlets were unevenly distributed by area socioeconomic status (SES). However, evidence from continental Europe is limited. This study aims to assess differences in tobacco outlet presence, density and proximity by area SES in the Netherlands. METHODS: All tobacco outlets in four Dutch cities (Amsterdam, and medium-sized cities Eindhoven, Haarlem, and Zwolle) were mapped between September 2019 and June 2020. We estimated associations between average property value of neighbourhoods (as an indicator of SES, grouped into quintiles) and (1) tobacco outlet presence in the neighbourhood (yes/no), (2) density (per km2), and (3) proximity to the closest outlet (in meters), using logistic and linear regression models. RESULTS: 46% of neighbourhoods contained at least one tobacco outlet. Tobacco outlets were mostly situated in city centres, but the distribution of tobacco outlets varied per city due to differences in urban structures and functions. In the medium-sized cities, each quintile higher neighbourhood-SES was associated with lower tobacco outlet presence (OR:0.71, 95%CI:0.59;0.85), lower density (B:-1.20 outlets/km2, 95%CI:-2.20;-0.20) and less proximity (B:40.2 m, 95%CI 36.58;43.83). Associations were the other way around for Amsterdam (OR:1.22, 95%CI:1.05;1.40, B:3.50, 95%CI:0.81;6.20, and B:-18.45, 95%CI:-20.41;-16.49, respectively). Results were similar for most types of tobacco outlets. CONCLUSION: In medium-sized cities in the Netherlands, tobacco outlets were more often located in low-SES neighbourhoods than high-SES. Amsterdam presented a reverse pattern, possibly due to its unique urban structure. We discuss how licensing might contribute to reducing tobacco outlets in low-SES neighbourhoods.

Bans on tobacco display, advertising and vending machines in the Netherlands: impact on visibility of tobacco and compliance of retailers.

INTRODUCTION: Visibility of tobacco products at retail tobacco outlets is associated with smoking initiation. To address this, across 2020-2022 the Netherlands banned tobacco product displays, advertisements and vending machines in the retail environment. Tobacco/vape specialist shops were exempted. This study assessed the impact of these policies on tobacco visibility in the retail environment and retailer compliance. METHODS: We conducted observational audits of all tobacco outlets in four Dutch cities (Amsterdam, Haarlem, Eindhoven and Zwolle) between 2019 and 2022 (before and after policy implementation), assessing visibility of tobacco products and advertisements, compliance and remaining sources of tobacco visibility (after implementation). We described results by location and outlet type. RESULTS: The number of tobacco outlets with any tobacco advertising or product visibility declined from 530 to 267 (-50%). Among outlets not exempt from the ban, the number with visibility declined from 449 to 172 (-62%), with lower postban visibility in petrol stations (12%) and supermarkets (6%) than small shops (47%). Visibility among tobacco/vape shops increased by 17%. Tobacco product displays remained the main source of visibility. 93% of tobacco vending machines were removed. Maps showed that non-compliance is concentrated in Amsterdam's city centre and more evenly distributed in other cities. CONCLUSION: The bans on tobacco display and tobacco advertising halved the visibility of tobacco in the retail environment, and the vending machine ban practically eradicated vending machines. To further reduce tobacco visibility, violations in small shops should be addressed and tobacco visibility should be regulated in currently exempt tobacco specialist shops.

The emergence of socioeconomic inequalities in smoking during adolescence and early adulthood.

BACKGROUND: While it is known that educational inequalities in smoking start during early and middle adolescence, it is unknown how they further develop until adulthood. The aim of this article is to map, in the Portuguese context, how educational inequalities in smoking emerge from pre-adolescence until young adulthood. METHODS: This study used longitudinal data from the EPITeen Cohort, which recruited adolescents enrolled in schools in Porto, Portugal. We included the 1,038 participants followed at ages 13 (2003/2004), 17, 21, and 24 years. We computed the odds ratio (OR) for the prevalence of smoking states (never smoking, experimenter, less-than-daily, daily and former smoker) and the incidence of transitions between these states, as function of age and education, stratified by sex. We also added interaction terms between age and education. RESULTS: Educational inequalities in daily smoking prevalence, with higher prevalence among those with lower educational level, emerged at 17 years old and persisted until higher ages. They were formed in a cumulative way by the increased risk of experimenting between 13 and 17 years, and increased risk of becoming daily smoker between 17 and 21 years. The incidence of smoking cessation was higher among the higher educated. Inequalities were formed similarly for women and men, but with lower level and showed no significance among women. CONCLUSIONS: These results highlight that actions to prevent smoking should also take in account the potential impact in smoking inequalities, and should focus not only on middle adolescence but also on late adolescence and early adulthood.

A Bispecific γδ T-cell Engager Targeting EGFR Activates a Potent Vγ9Vδ2 T cell-Mediated Immune Response against EGFR-Expressing Tumors.

Vγ9Vδ2 T cells are effector cells with proven antitumor efficacy against a broad range of cancers. This study aimed to assess the antitumor activity and safety of a bispecific antibody directing Vγ9Vδ2 T cells to EGFR-expressing tumors. An EGFR-Vδ2 bispecific T-cell engager (bsTCE) was generated, and its capacity to activate Vγ9Vδ2 T cells and trigger antitumor activity was tested in multiple in vitro, in vivo, and ex vivo models. Studies to explore safety were conducted using cross-reactive surrogate engagers in nonhuman primates (NHP). We found that Vγ9Vδ2 T cells from peripheral blood and tumor specimens of patients with EGFR+ cancers had a distinct immune checkpoint expression profile characterized by low levels of PD-1, LAG-3, and TIM-3. Vγ9Vδ2 T cells could be activated by EGFR-Vδ2 bsTCEs to mediate lysis of various EGFR+ patient-derived tumor samples, and substantial tumor growth inhibition and improved survival were observed in in vivo xenograft mouse models using peripheral blood mononuclear cells (PBMC) as effector cells. EGFR-Vδ2 bsTCEs exerted preferential activity toward EGFR+ tumor cells and induced downstream activation of CD4+ and CD8+ T cells and natural killer (NK) cells without concomitant activation of suppressive regulatory T cells observed with EGFR-CD3 bsTCEs. Administration of fully cross-reactive and half-life extended surrogate engagers to NHPs did not trigger signals in the safety parameters that were assessed. Considering the effector and immune-activating properties of Vγ9Vδ2 T cells, the preclinical efficacy data and acceptable safety profile reported here provide a solid basis for testing EGFR-Vδ2 bsTCEs in patients with EGFR+ malignancies.

Perfluorocarbon Nanoemulsions with Fluorous Chlorin-Type Photosensitizers for Antitumor Photodynamic Therapy in Hypoxia.

The efficacy of photodynamic therapy (PDT) strictly depends on the availability of molecular oxygen to trigger the light-induced generation of reactive species. Fluorocarbons have an increased ability to dissolve oxygen and are attractive tools for gas delivery. We synthesized three fluorous derivatives of chlorin with peripheral polyfluoroalkyl substituents. These compounds were used as precursors for preparing nanoemulsions with perfluorodecalin as an oxygen depot. Therefore, our formulations contained hydrophobic photosensitizers capable of absorbing monochromatic light in the long wavelength region and the oxygen carrier. These modifications did not alter the photosensitizing characteristics of chlorin such as the generation of singlet oxygen, the major cytocidal species in PDT. Emulsions readily entered HCT116 colon carcinoma cells and accumulated largely in mitochondria. Illumination of cells loaded with emulsions rapidly caused peroxidation of lipids and the loss of the plasma membrane integrity (photonecrosis). Most importantly, in PDT settings, emulsions potently sensitized cells cultured under prolonged (8 weeks) hypoxia as well as cells after oxygen depletion with sodium sulfite (acute hypoxia). The photodamaging potency of emulsions in hypoxia was significantly more pronounced compared to emulsion-free counterparts. Considering a negligible dark cytotoxicity, our materials emerge as efficient and biocompatible instruments for PDT-assisted eradication of hypoxic cells.

The COVID-19 pandemic and temporal change in metabolic risk factors for cardiovascular disease: A natural experiment within the HELIUS study.

The coronavirus disease 2019 (COVID-19) pandemic, including the restrictive measures taken to reduce the spread of the virus, negatively affected people's health behavior. We explored whether the pandemic also had an effect on metabolic risk factors for cardiovascular disease (CVD) in women and men. We conducted a natural experiment, using data from 6962 participants without CVD at baseline (2011-2015) of six ethnic groups of the HELIUS study in Amsterdam, the Netherlands. We studied whether participants whose follow-up measurements were taken within the 11 months before the pandemic (control group) differed from those whose measurements were taken taken within 6 months after the first lockdown (exposed group). Using sex-stratified linear regressions with inverse probability weighting, we compared changes in baseline- and follow-up data between the control and exposed group in six metabolic risk factors: systolic and diastolic blood pressure (SBP, DBP), total cholesterol (TC), fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), and estimated glomerular filtration rate (eGFR). Next, we explored the mediating effect of changes in body-mass index (BMI), alcohol, smoking, depressive symptoms and negative life events at follow-up. We observed less favorable changes in SBP (+1.12mmHg for women, +1.38mmHg for men), DBP (+0.85mmHg, +0.80mmHg) and FPG (only in women, +0.12 mmol/L) over time in the exposed group relative to the control group. Conversely, changes in HbA1c (-0.65 mmol/mol, -0.84 mmol/mol) and eGFR (+1.06 mL/min, +1.04 mL/min) were more favorable in the exposed compared to the control group, respectively. Changes in SBP, DBP, and FPG were partially mediated by changes in behavioral factors, in particular BMI and alcohol consumption. Concluding, the COVID-19 pandemic, in particular behavioral changes associated with restrictive lockdown measures, may have negatively affected several CVD risk factors, in both women and men.

Lesson-drawing in tobacco control: A qualitative study of stakeholder perceptions in five North-Western European countries.

INTRODUCTION: The theory of 'family of nations' posits that countries draw policy lessons predominantly from similar countries. Lesson-drawing in tobacco control has, however, been primarily studied in the 'English-speaking' family. We examined in five diverse North-Western European countries whether the government engages in lesson-drawing regarding best practices in tobacco control, which countries they look at for guidance, and why these were chosen as a reference. METHODS: Perceptions of 29 policy participants from civil society and government were assessed by means of interviews conducted in Belgium, Finland, Germany, Ireland, and the Netherlands. Relevant excerpts were grouped according to country and a bottom-up thematic analysis was performed. RESULTS: The tobacco control instruments described by the policy participants were tobacco marketing bans (display ban and plain packaging) and smoke-free policies. German interviewees stated that the German federal government is not inclined to engage in foreign lesson-drawing. All other governments were perceived to look at Australia for lessons because of its global leadership in tobacco control. At the same time however, lessons from Australia were easily dismissed because it is an 'island' and far away. Irish interviewees observed their government to primarily look at other English-speaking countries. Governments in Belgium, Finland and the Netherlands were observed to primarily look at nearby European countries for lessons. CONCLUSIONS: Countries in North-Western Europe seem to draw policy lessons based on proximity and similarity to other countries concerning marketing bans and smoke-free policies. Proponents of tobacco control may use these findings to facilitate effective lesson-drawing in their countries.

A bispecific T cell engager recruits both type 1 NKT and Vγ9Vδ2-T cells for the treatment of CD1d-expressing hematological malignancies.

Bispecific T cell engagers (bsTCEs) hold great promise for cancer treatment but face challenges due to the induction of cytokine release syndrome (CRS), on-target off-tumor toxicity, and the engagement of immunosuppressive regulatory T cells that limit efficacy. The development of Vγ9Vδ2-T cell engagers may overcome these challenges by combining high therapeutic efficacy with limited toxicity. By linking a CD1d-specific single-domain antibody (VHH) to a Vδ2-TCR-specific VHH, we create a bsTCE with trispecific properties, which engages not only Vγ9Vδ2-T cells but also type 1 NKT cells to CD1d+ tumors and triggers robust proinflammatory cytokine production, effector cell expansion, and target cell lysis in vitro. We show that CD1d is expressed by the majority of patient MM, (myelo)monocytic AML, and CLL cells and that the bsTCE triggers type 1 NKT and Vγ9Vδ2-T cell-mediated antitumor activity against these patient tumor cells and improves survival in in vivo AML, MM, and T-ALL mouse models. Evaluation of a surrogate CD1d-γδ bsTCE in NHPs shows Vγ9Vδ2-T cell engagement and excellent tolerability. Based on these results, CD1d-Vδ2 bsTCE (LAVA-051) is now evaluated in a phase 1/2a study in patients with therapy refractory CLL, MM, or AML.

The contribution of smoking to differences in cardiovascular disease incidence between men and women across six ethnic groups in Amsterdam, the Netherlands: The HELIUS study.

It is unclear to what extent differences in cardiovascular disease (CVD) risk between men and women are explained by differences in smoking, and whether this contribution to risk is consistent across ethnic groups. In this prospective study, we determined the contribution of smoking to differences in CVD incidence between men and women, also in various ethnic groups. We linked baseline data of 18,058 participants of six ethnic groups from the HELIUS study (Amsterdam, the Netherlands) to CVD incidence data, based on hospital admission and death records from Statistics Netherlands (2013-2019). The contribution of smoking to CVD incidence, as estimated by the population attributable fraction, was higher in men than in women, overall (24.1% versus 15.6%) and across most ethnic groups. Among Dutch participants, however, the contribution of smoking was higher among women (21.0%) than men (16.2%). Using Cox regression analyses, we observed that differences in smoking prevalence explained 22.0% of the overall lower hazard for CVD in women compared to men. Smoking contributed minimally to the lower hazards for CVD in women among participants of Dutch (0%), Ghanaian (4.9%) and Moroccan origin (0%), but explained 28.6% and 48.6% of the lower hazards in women in South-Asian Surinamese and African Surinamese groups, respectively. While smoking prevention and cessation may lead to lower CVD incidence in most groups of men and women, it may not substantially reduce disparities in CVD risk between men and women in most ethnic groups.

Mechanisms of Phototoxic Effects of Cationic Porphyrins on Human Cells In Vitro.

The toxic effects of four cationic porphyrins on various human cells were studied in vitro. It was found that, under dark conditions, porphyrins are almost nontoxic, while, under the action of light, the toxic effect was observed starting from nanomolar concentrations. At a concentration of 100 nM, porphyrins caused inhibition of metabolism in the MTT test in normal and cancer cells. Furthermore, low concentrations of porphyrins inhibited colony formation. The toxic effect was nonlinear; with increasing concentrations of various porphyrins, up to about 1 µM, the effect reached a plateau. In addition to the MTT test, this was repeated in experiments examining cell permeability to trypan blue, as well as survival after 24 h. The first visible manifestation of the toxic action of porphyrins is blebbing and swelling of cells. Against the background of this process, permeability to porphyrins and trypan blue appears. Subsequently, most cells (even mitotic cells) freeze in this swollen state for a long time (24 and even 48 h), remaining attached. Cellular morphology is mostly preserved. Thus, it is clear that the cells undergo mainly necrotic death. The hypothesis proposed is that the concentration dependence of membrane damage indicates a limited number of porphyrin targets on the membrane. These targets may be any ion channels, which should be considered in photodynamic therapy.

A Novel Methodological Approach to Measure Linear Trends in Health Inequalities: Proof of Concept With Adolescent Smoking in Europe.

We describe a new method for presenting and interpreting linear trends in health inequalities, and present a proof-of-concept analysis of inequalities in smoking among adolescents in Europe. We estimated the regression line of the assumed linear relationship between smoking prevalence in low- and high-socioeconomic status (SES) youth over time. Using simulation, we constructed a 95% confidence interval (CI) for the smoking prevalence in low-SES youth for when this would be 0% in high-SES youth, and we calculated the likelihood of eradicating smoking inequality (<5% for both low and high SES). This method was applied to data on adolescents aged 15-16 years (n = 250,326) from 23 European countries, derived from the 2003-2015 European Survey Project on Alcohol and Other Drugs. Smoking prevalence decreased more slowly among low- than among high-SES adolescents. The estimated smoking prevalence was 9.4% (95% CI: 6.1, 12.7) for boys and 5.4% (95% CI: 1.4, 9.2) for girls with low SES when 0% with high SES. The likelihood of eradicating smoking inequality was <1% for boys and 37% for girls. We conclude that this novel methodological approach to trends in health inequalities is feasible in practice. Applying it to trends in smoking inequalities among adolescents in Europe, we found that Europe is currently not on track to eradicate youth smoking across SES groups.

The Diffusion of Smoking: Association Between School Tobacco Policies and the Diffusion of Adolescent Smoking in 38 Schools in 6 Countries.

Social network research has evidenced the role of peer effects in the adoption of behaviours. Little is known, however, about whether policies affect how behaviours are shared in a network. To contribute to this literature, we apply the concept of diffusion centrality to school tobacco policies and adolescent smoking. Diffusion centrality is a measure of centrality which refers to a person's ability to diffuse a given property-in our case, smoking-related behaviours. We hypothesized that stronger school tobacco policies are associated with less diffusion centrality of smoking on school premises and of smoking in general. A whole network study was carried out in 2013 and 2016 among adolescents (n = 18,805) in 38 schools located in six European cities. Overall, diffusion centrality of smoking in general and of smoking on school premises significantly decreased over time. Diffusion centrality of smoking significantly decreased both in schools where the policy strengthened or softened over time, but for diffusion of smoking on school premises, this decrease was only significant in schools where it strengthened. Finally, stronger school tobacco policies were associated with lower diffusion centrality of smoking on school premises and of smoking in general, though to a lesser extent. With such policies, smoking may, therefore, become less prevalent, less popular, and less clustered, thereby lowering the risk of it spreading within networks in, and even outside the school.