Radioluminescent nanoparticles for radiation-controlled release of drugs

The present work demonstrates a novel concept for intratumoral chemo-radio combination therapy for locally advanced solid tumors. For some locally advanced tumors, chemoradiation is currently standard of care. This combination treatment can cause acute and long term toxicity that can limit its use in older patients or those with multiple medical comorbidities. Intratumoral chemotherapy has the potential to address the problem of systemic toxicity that conventional chemotherapy suffers, and may, in our view, be a better strategy for treating certain locally advanced tumors. The present study proposes how intratumoral chemoradiation can be best implemented. The enabling concept is the use of a new chemotherapeutic formulation in which chemotherapy drugs (e.g., paclitaxel (PTX)) are co-encapsulated with radioluminecsnt nanoparticles (e.g., CaWO4 (CWO) nanoparticles (NPs)) within protective capsules formed by biocompatible/biodegradable polymers (e.g., poly(ethylene glycol)-poly(lactic acid) or PEG-PLA). This drug-loaded polymer-encapsulated radioluminescent nanoparticle system can be locally injected in solution form into the patient's tumor before the patient receives normal radiotherapy (e.g., 30–40 fractions of 2–3 Gy daily X-ray dose delivered over several weeks for locally advanced head and neck tumors). Under X-ray irradiation, the radioluminescent nanoparticles produce UV-A light that has a radio-sensitizing effect. These co-encapsulated radioluminescent nanoparticles also enable radiation-triggered release of chemo drugs from the polymer coating layer. The non-toxic nature (absence of dark toxicity) of this drug-loaded polymer-encapsulated radioluminescent nanoparticle (“PEG-PLA/CWO/PTX”) formulation was confirmed by the MTT assay in cancer cell cultures. A clonogenic cell survival assay confirmed that these drug-loaded polymer-encapsulated radioluminescent nanoparticles significantly enhance the cancer cell killing effect of radiation therapy. In vivo study validated the efficacy of PEG-PLA/CWO/PTX-based intratumoral chemo-radio therapy in mouse tumor xenografts (in terms of tumor response and mouse survival). Results of a small-scale NP biodistribution (BD) study demonstrate that PEG-PLA/CWO/PTX NPs remained at the tumor sites for a long period of time (> 1 month) following direct intratumoral administration. A multi-compartmental pharmacokinetic model (with rate constants estimated from in vitro experiments) predicts that this radiation-controlled drug release technology enables significant improvements in the level and duration of drug availability within the tumor (throughout the typical length of radiation treatment, i.e., > 1 month) over conventional delivery systems (e.g., PEG-PLA micelles with no co-encapsulated CaWO4, or an organic liquid, e.g., a 50:50 mixture of Cremophor EL and ethanol, as in Taxol), while it is capable of maintaining the systemic level of the chemo drug far below the toxic threshold limit over the entire treatment period. This technology thus has the potential to offer a new therapeutic option that has not previously been available for patients excluded from conventional chemoradiation protocols

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Sociodemographics of pet ownership among adolescents in Great Britain: findings from the HBSC study in England, Scotland, and Wales

The aim of this study was to assess the prevalence of pet ownership among adolescents in Great Britain and identify any sociodemographic differences between pet owners and non-pet owners. A total of 14,328 11-to 15-year-old adolescents from England, Scotland, and Wales were included in the analysis. Results revealed 15-year-old adolescents were significantly more likely than 11-year-old adolescents to own dogs (OR = 1.146, p < 0.001) but less likely to own fish, reptiles, or amphibians (OR = 0.629, p < 0.001), and small mammals (OR = 0.630, p < 0.001). Thirteen-year-olds were significantly more likely than 11-year-olds to own dogs (OR = 1.240, p = 0.021) and birds (OR = 1.299, p = 0.010), but significantly less likely to own fish, reptiles, or amphibians (OR = 0.795, p < 0.001). No gender differences were found. White adolescents were more likely than non-white adolescents to own all pet types. Those living in single-parent families were significantly more likely than those living with two parents to own dogs (OR = 1.186, p = 0.013) and cats (OR = 1.319, p < 0.001). Furthermore, those who reported living in stepfamilies were also more likely to own cats (OR = 1.428, p < 0.001). Adolescents with siblings were more likely to own cats (OR = 1.391, p = 0.001), fish, reptiles, or amphibians (OR = 1.220, p = 0.037) than adolescents without siblings. Adolescents with employed parents (both or one) were significantly more likely than those with unemployed parents to own dogs (OR = 1.414, p = 0.002) and birds (OR = 1.523, p = 0.018). Adolescents from high-affluence families were less likely than adolescents from low-affluence families to own dogs (OR = 0.888, p = 0.037), small mammals (OR = 0.832, p = 0.005), and birds (OR = 0.801, p = 0.046). Furthermore, family affluence differences were found in different pet types. Differences in all pet types and siblings were also found in a proxy measure of attachment to pets. This study provides evidence that pet ownership is related to several sociodemographic factors. These are relevant to take into account when performing HAI studies on adolescents.Peer reviewe

Quality, features, and presence of behavior change techniques in mobile Apps designed to improve physical activity in pregnant women: Systematic search and content analysis

BACKGROUND: Physical activity during pregnancy is associated with several health benefits for the mother and child. However, very few women participate in regular physical activity during pregnancy. eHealth platforms (internet and mobile apps) have become an important information source for pregnant women. Although the use of pregnancy-related apps has significantly increased among pregnant women, very little is known about their theoretical underpinnings, including their utilization of behavior change techniques (BCTs). This is despite research suggesting that inclusion of BCTs in eHealth interventions are important for promoting healthy behaviors, including physical activity. OBJECTIVE: The aim of this study was to conduct a systematic search and content analysis of app quality, features, and the presence of BCTs in apps designed to promote physical activity among pregnant women. METHODS: A systematic search in the Australian App Store and Google Play store using search terms relating to exercise and pregnancy was performed. App quality and features were assessed using the 19-item Mobile App Rating Scale (MARS), and a taxonomy of BCTs was used to determine the presence of BCTs (26 items). BCTs previously demonstrating efficacy in behavior changes during pregnancy were also identified from a literature review. Spearman correlations were used to investigate the relationships between app quality, app features, and number of BCTs identified. RESULTS: Nineteen exercise apps were deemed eligible for this review and they were accessed via Google Play (n=13) or App Store (n=6). The MARS overall quality scores indicated moderate app quality (mean 3.5 [SD 0.52]). Functionality was the highest scoring MARS domain (mean 4.2 [SD 0.5]), followed by aesthetics (mean 3.7 [SD 0.6]) and information quality (mean 3.16 [SD 0.42]). Subjective app quality (mean 2.54 [SD 0.64]) and likelihood for behavioral impact (mean 2.5 [SD 0.6]) were the lowest scoring MARS domains. All 19 apps were found to incorporate at least two BCTs (mean 4.74, SD 2.51; range 2-10). However, only 11 apps included BCTs that previously demonstrated efficacy for behavior change during pregnancy, the most common being provide opportunities for social comparison (n=8) and prompt self-monitoring of behavior (n=7). There was a significant positive correlation between the number of BCTs with engagement and aesthetics scores, but the number of BCTs was not significantly correlated with functionality, information quality, total MARS quality, or subjective quality. CONCLUSIONS: Our findings showed that apps designed to promote physical activity among pregnant women were functional and aesthetically pleasing, with overall moderate quality. However, the incorporation of BCTs was low, with limited prevalence of BCTs previously demonstrating efficacy in behavior change during pregnancy. Future app development should identify and adopt factors that enhance and encourage user engagement, including the use of BCTs, especially those that have demonstrated efficacy for promoting physical activity behavior change among pregnant women

Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease

Up to 30% of adult patients with sickle cell disease (SCD) will develop pulmonary hypertension (pHTN), a complication associated with significant morbidity and mortality. To identify genetic factors that contribute to risk for pHTN in SCD, we performed association analysis with 297 single nucleotide polymorphisms (SNPs) in 49 candidate genes in patients with sickle cell anemia (Hb SS) who had been screened for pHTN by echocardiography (n = 111). Evidence of association was primarily identified for genes in the TGFβ superfamily, including activin A receptor, type II–like 1 (ACVRL1), bone morphogenetic protein receptor 2 (BMPR2), and bone morphogenetic protein 6 (BMP6). The association of pHTN with ACVRL1 and BMPR2 corroborates the previous association of these genes with primary pHTN. Moreover, genes in the TGFβ pathway have been independently implicated in risk for several sickle cell complications, suggesting that this gene pathway is important in overall sickle cell pathophysiology. Genetic variation in the β-1 adrenergic receptor (ADRB1) was also associated with pHTN in our dataset. A multiple regression model, which included age and baseline hemoglobin as covariates, retained SNPs in ACVRL1, BMP6, and ADRB1 as independently contributing to pHTN risk. These findings may offer new promise for identifying patients at risk for pHTN, developing new therapeutic targets, and reducing the occurrence of this life-threatening SCD complication

Moral Narratives Workshop Proceedings

The Moral Narratives Workshop (www. moralnarratives.org) was organized in 2022 to kickstart and develop an interdisciplinary, empirical study of stories told about people’s moral actions and characters. Across eight weeks, the workshop featured talks on topics such as the cognitive mechanisms of moral narrative construction (e.g., narrator’s goals, pragmatic inferences, the role of audiences, deception), the various functions of moral narratives (e.g., cultural/master narratives, narrative identity, understanding, legitimization and maintenance of power, persuasion, autobiographical memory, victimizing, redemption, moral development), featuring cases of moral narratives in various contexts (e.g., criminal justice, propaganda, politics, journalism, literature, science communication). Each talk was followed by an hour-long group discussion expanding on the themes of the talks. Participants came from diverse backgrounds, including psychology, philosophy, linguistics, communications, journalism, literature, political science, and anthropology. Here, we provide a record of the insights arising from the group discussions. Its contents faithfully reflect the diversity, complexity and messiness of human knowledge production. We intend for these workshop proceedings to serve as a rich and generative resource for future scholarship on moral narratives

The influence of social support on ethnic differences in well-being and depression in adolescents: findings from the prospective Olympic Regeneration in East London (ORiEL) study.

PURPOSE: This study examines the extent to which in adolescent positive mental well-being and depressive symptoms vary across ethnic groups, and prospectively examines whether social support is protective against low/poor well-being and depression. METHODS: A longitudinal survey of 2426 adolescents from the Olympic Regeneration in East London study measured well-being and depressive symptoms at baseline at ages 11-12 and at follow-up two years later at ages 13-14. Social support was assessed at ages 11-12 years by the Multidimensional Scale of Perceived Social Support, by the level of parental support for school, by the frequency of family activities and by friendship choices. Ethnic differences in well-being and depression in Bangladeshi (N = 337) and Black African (N = 249) adolescents compared to their White UK counterparts (N = 380) were estimated adjusted stepwise for socio-demographic factors and domains of social support. RESULTS: Black African and Bangladeshi adolescents scored significantly higher for well-being than their White UK counterparts. There were no significant ethnic differences in the prevalence of depressive symptoms. Lower levels of social support were prospectively associated with lower well-being and higher rates of depression in all ethnic groups. Adjustment for multiple domains of social support did not account for ethnic differences in well-being. CONCLUSION: Bangladeshi and Black African adolescents in East London may have a positive mental health advantage over their White UK counterparts though social support did not fully explain this difference. Further investigation of the reasons for lower well-being in the White UK group is needed