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Abstract Background Injectable opioid agonist treatment (iOAT) is an effective option to support people living with opioid use disorder (OUD) who have not sufficiently benefitted from oral OAT. However, iOAT has been criticised based on theoretical and practical grounds for its dosing policies: Current regulations demand supervised, on-site application and require patients to frequently visit their treatment facility. The current study aims to investigate how patients experience on-site application and derive strategies to enhance the acceptability and effectiveness of iOAT-delivery. Methods This article is based on semi-structured interviews with 27 individuals currently or previously in iOAT in two German outpatient iOAT-clinics. We undertook an inductive qualitative content analysis, which included blinded, independent coding and the analysis of individual cases. Results Comments regarding on-site application and daily visits to the clinic were grouped into positive and negative aspects, iOAT as the best alternative option, facilitators of daily visits, and suggestions for improvement. Positive aspects took the factors stability and social support in regard. Negative aspects ranged from general inconveniences to major impediments to individuals' daily lives and towards achieving psychosocial goals. Participants reported rigorous adherence to iOAT's treatment regime, often due to a perceived lack of alternative options. Meeting iOAT's demands was eased by the patients’ coping-strategies and through facilitating measures implemented by iOAT-clinics. Despite acknowledgement of the potential detriments from easing regulations, take-home arrangements were frequently suggested by participants to improve iOAT. Conclusions Being required to attend the clinic for supervised iOAT-application is not experienced uniformly. While clinics can support their patients to cope with strict regulations, alternative approaches to iOAT-application should be considered to accommodate patients' individual needs. Examples from other treatment modalities (e.g., remote supervision and delivery services) might aid to reconcile individualisation while providing adequate safety measures and improve iOAT in the long term.

Abstract Background Intrinsic fitness costs are likely to have guided the selection of lineage-determining mutations during emergence of variants of SARS-CoV-2. Whereas changes in receptor affinity and antibody neutralization have been thoroughly mapped for individual mutations in spike, their influence on intrinsic replicative fitness remains understudied. Methods We analyzed mutations in immunodominant spike epitope E484 that became temporarily fixed over the pandemic. We engineered the resulting immune escape mutations E484K, -A, and -Q in recombinant SARS-CoV-2. We characterized viral replication, entry, and competitive fitness with and without immune serum from humans with defined exposure/vaccination history and hamsters monospecifically infected with the E484K variant. We additionally engineered a virus containing the Omicron signature mutations N501Y and Q498R that were predicted to epistatically enhance receptor binding. Results Multistep growth kinetics in Vero-, Calu-3, and NCI-H1299 were identical between viruses. Synchronized entry experiments based on cold absorption and temperature shift identified only an insignificant trend toward faster entry of the E484K variant. Competitive passage experiments revealed clear replicative fitness differences. In absence of immune serum, E484A and E484Q, but not E484K, were replaced by wildtype (WT) in competition assays. In presence of immune serum, all three mutants outcompeted WT. Decreased E484A fitness levels were over-compensated for by N501Y and Q498R, identifying a putative Omicron founder background that exceeds the intrinsic and effective fitness of WT and matches that of E484K. Critically, the E484A/Q498R/N501Y mutant and E484K have equal fitness also in presence of pre-Omicron vaccinee serum, whereas the fitness gain by E484K is lost in the presence of serum raised against the E484K variant in hamsters. Conclusions The emergence of E484A and E484Q prior to widespread population immunity may have been limited by fitness costs. In populations already exposed to the early immune escape epitope E484K, the Omicron founder background may have provided a basis for alternative immune escape evolution via E484A. Studies of major antigenic epitope changes with and without their epistatic context help reconstruct the sequential adjustments of intrinsic fitness versus neutralization escape during the evolution of major SARS-CoV-2 variants in an increasingly immune human population.

Abstract Background Research conducted in urban areas has highlighted the impact of housing instability on people who inject drugs (PWID), revealing that it exacerbates vulnerability to drug-related harms and impedes syringe service program (SSP) use. However, few studies have explored the effects of houselessness on SSP use among rural PWID. This study examines the relationship between houselessness and SSP utilization among PWID in eight rural areas across 10 states. Methods PWID were recruited using respondent-driven sampling for a cross-sectional survey that queried self-reported drug use and SSP utilization in the prior 30 days, houselessness in the prior 6 months and sociodemographic characteristics. Using binomial logistic regression, we examined the relationship between experiencing houselessness and any SSP use. To assess the relationship between houselessness and the frequency of SSP use, we conducted multinomial logistic regression analyses among participants reporting any past 30-day SSP use. Results Among 2394 rural PWID, 56.5% had experienced houselessness in the prior 6 months, and 43.5% reported past 30-day SSP use. PWID who had experienced houselessness were more likely to report using an SSP compared to their housed counterparts (adjusted odds ratio [aOR] = 1.24 [95% confidence intervals [CI] 1.01, 1.52]). Among those who had used an SSP at least once (n = 972), those who experienced houselessness were just as likely to report SSP use two (aOR = 0.90 [95% CI 0.60, 1.36]) and three times (aOR = 1.18 [95% CI 0.77, 1.98]) compared to once. However, they were less likely to visit an SSP four or more times compared to once in the prior 30 days (aOR = 0.59 [95% CI 0.40, 0.85]). Conclusion This study provides evidence that rural PWID who experience houselessness utilize SSPs at similar or higher rates as their housed counterparts. However, housing instability may pose barriers to more frequent SSP use. These findings are significant as people who experience houselessness are at increased risk for drug-related harms and encounter additional challenges when attempting to access SSPs.

Abstract Pet ownership has been associated with reduced deterioration in physical health as older adults age; little research focused on deterioration in cognitive function. We examine the relationship of pet, dog, cat ownership, and dog walking to changes in cognitive function among 637 generally healthy community-dwelling older adults (185 pet owners) aged 50–100 years (M = 68.3, SD = 9.6) within the BLSA. Cognitive assessments every 1–4 years over 1–13 years (M = 7.5, SD = 3.6) include the California Verbal Learning (Immediate, Short, Long Recall); Benton Visual Retention; Trail-Making (Trails A, B, B-A); Digit Span; Boston Naming (Naming); and Digit Symbol Substitution (Digit Symbol) Tests. In linear mixed models, deterioration in cognitive function with age was slower for pet owners than non-owners (Immediate, Short, Long Recall; Trails A,B,B-A; Naming; Digit Symbol); dog owners than non-owners (Immediate, Short Recall; Trails A,B; Naming; Digit Symbol); and cat owners than non-owners (Immediate, Short, Long Recall; Naming), controlling for age and comorbidities. Among dog owners (N = 73) walkers experienced slower deterioration than non-walkers (Trails B, B-A; Short Recall). All ps ≤ 0.05. We provide important longitudinal evidence that pet ownership and dog walking contribute to maintaining cognitive function with aging and the need to support pet ownership and dog walking in design of senior communities and services.

Today, the built environment, including infrastructure for tunnels, bridges, highways, subways, railroads, harbors, buildings and airports, is responsible for a significant portion of the energy consumption, natural resource utilization, waste generation as well as CO2 and other environmentally harmful emissions in the United States and around the world. There is no silver bullet solution to achieve the ambitious goal of zero carbon buildings and a city infrastructure with significantly reduced CO2 emissions. Thus, multifaceted solutions should be developed. Another challenge associated with the built environment is aging and a large economic burden to upgrade and maintain the outdated infrastructure. The current status of the U.S. built environment is far below sustainable condition. Rapidly deteriorating infrastructure that must be replaced provides us with the unique opportunity to rethink where and how we should live in the future. In addition, current challenges related to economic and societal inequality in the United States and other global communities also force us to re-evaluate how humanity is connected and how we share resources for a sustainable and healthy future while keeping the Earth safe. The engineering solutions for our future built environment include, but are not limited to, the design and synthesis of new infrastructure materials with low carbon intensity, the development of new manufacturing options and technologies, and the integration of innovative functionalities into building envelopes.

BackgroundOver nearly three years, the COVID-19 pandemic has had a lasting impact on people's lives and mental health worldwide with its far-reaching restrictions and concerns about infections and other personal consequences. Families were particularly affected and showed increased stress and psychological problems. Long-term effects cannot be ruled out. So far, data on young families are sparse. The present longitudinal analysis (n = 932) of the CoronabaBY study investigated the development of parenting stress, parental affective symptoms, and child's mental health in young families with children aged 0–3 years in Germany as well as potential influencing factors.MethodsThe observational study includes two measurement points over the course of the pandemic (baseline and follow-up). Data was collected by app using standardized questionnaires.ResultsN = 932 participants, mainly mothers (94.7%) born in Germany (93.1%) with higher education (61.3% with at least high school diploma) and a comfortable financial situation participated in the longitudinal study. Children were on average 14.7 months old at baseline (SD: 12, range: 1–39 months). While the proportion of parents who perceived the pandemic as stressful decreased significantly from baseline (60%) to follow-up (52.3%), the proportion with parenting stress increased significantly (from 40.1% to 45.4%). Both parental and child mental health problems remained constant over time, with infants crying/feeding/sleeping problems ranging above pre-pandemic comparative data. Most predictive for high parenting stress at follow-up was high parenting stress at baseline. This was also true for parental affective symptoms (depression/anxiety) and child mental health problems.ConclusionsDespite faded pandemic restrictions, parents remained burdened. Support services do not appear to have been sufficient to help families out of their stressful situation. Our results indicate a need for action regarding low-threshold services that effectively reach affected families.Trial registrationThe study was pre-registered in OSF (https://osf.io/search/?q=tksh5&page=1).

Abstract Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR‐activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN‐amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the antiferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc−. The identification of LRP8 as a specific vulnerability of MYCN‐amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet‐unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high‐risk neuroblastoma and potentially other MYCN‐amplified entities.