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BackgroundCigarette smoking continues to be a leading cause of preventable deaths in the USA, in part because the USA has not adopted the WHO Framework Convention on Tobacco Control. One way the tobacco industry counteracts tobacco control policies is by heavily advertising cigarettes at the point of sale in retailers (eg, at the cash register) and by offering discounts on cigarettes.DesignA within-subject experimental design with adults who smoke cigarettes daily (n=281) investigated whether: (1) exposure to images of cigarette promotions in an online experiment is associated with greater cigarette craving relative to viewing images of non-smoking cues, and (2) if exposure to images of point-of-sale cigarette promotions with a discount (vs without) increases cigarette craving. The study also examined how participants’ subjective social status (compared with others in the USA) relates to cigarette craving after exposure to images of cigarette promotions with and without a discount.ResultsIn an online experiment, exposure to images of smoking cues, including point-of-sale cigarette promotions, elicited greater craving relative to non-smoking cues (all p<0.001). In addition, images of promotions with a discount elicited higher levels of craving compared with those without a discount (b=0.09, p=0.001). Although participants with a higher (vs lower) subjective social status craved cigarettes less overall (b=−0.12, p=0.012), there was no difference in their craving between images of promotions with and without a discount, while craving was higher for images of promotions with a discount than without for participants with higher subjective social status (b=0.06, p=0.021).ConclusionViewing images of point-of-sale cigarette promotions can causally increase cravings to smoke, which may also apply to real-world retail settings that display cigarette promotions. Restricting point-of-sale promotions generally, and discounts specifically, could help reduce cigarette smoking and address tobacco use disparities in the USA.

Well-informed individual and collective decision-making is aided by access to high-quality, factual information. What motivates people to share high-quality news, and how can these motives be leveraged to promote news sharing? Based on the theory that self-related and social motives encourage sharing behavior, we designed and tested interventions to increase news sharing. In the interventions, individuals were exposed to actual news stories and were prompted to identify why the content was relevant to themselves (self-relevance) or people they know (social relevance). Across four studies (Nparticipants = 2,559, Nobservations = 18,780), we systematically examined the effectiveness of these interventions, their generalizability across news topics (climate change and health) and cultures (the United States of America and the Netherlands), their translation to more naturalistic contexts, and their underlying neuropsychological mechanisms. In all studies, we observed expected positive correlations among perceived self and social relevance and sharing intentions. In a neuroimaging study, we also observed corresponding increases in activity in self-referential and social cognitive brain regions. Using the content-framing interventions to test causal relationships, we found that the interventions increased sharing intentions and behavior. Furthermore, we observed generalizability across news topics and cultural contexts and translation to an ecologically valid news exposure context. These findings advance theory by adding neural and behavioral evidence that self-related and social motives prompt people to share information, and demonstrate the ability of content-framing interventions to harness these motives to encourage high-quality news sharing.

We present the Progression and Transmission of HIV (PATH 4.0), a simulation tool for analyses of cluster detection and intervention strategies. Molecular clusters are groups of HIV infections that are genetically similar, indicating rapid HIV transmission where HIV prevention resources are needed to improve health outcomes and prevent new infections. PATH 4.0 was constructed using a newly developed agent-based evolving network modeling (ABENM) technique and evolving contact network algorithm (ECNA) for generating scale-free networks. ABENM and ECNA were developed to facilitate simulation of transmission networks for low-prevalence diseases, such as HIV, which creates computational challenges for current network simulation techniques. Simulating transmission networks is essential for studying network dynamics, including clusters. We validated PATH 4.0 by comparing simulated projections of HIV diagnoses with estimates from the National HIV Surveillance System (NHSS) for 2010–2017. We also applied a cluster generation algorithm to PATH 4.0 to estimate cluster features, including the distribution of persons with diagnosed HIV infection by cluster status and size and the size distribution of clusters. Simulated features matched well with NHSS estimates, which used molecular methods to detect clusters among HIV nucleotide sequences of persons with HIV diagnosed during 2015–2017. Cluster detection and response is a component of the U.S. Ending the HIV Epidemic strategy. While surveillance is critical for detecting clusters, a model in conjunction with surveillance can allow us to refine cluster detection methods, understand factors associated with cluster growth, and assess interventions to inform effective response strategies. As surveillance data are only available for cases that are diagnosed and reported, a model is a critical tool to understand the true size of clusters and assess key questions, such as the relative contributions of clusters to onward transmissions. We believe PATH 4.0 is the first modeling tool available to assess cluster detection and response at the national-level and could help inform the national strategic plan.

Background PREDICT is a breast cancer prognostic and treatment benefit model implemented online. The overall fit of the model has been good in multiple independent case series, but PREDICT has been shown to underestimate breast cancer specific mortality in women diagnosed under the age of 40. Another limitation is the use of discrete categories for tumour size and node status resulting in ‘step’ changes in risk estimates on moving between categories. We have refitted the PREDICT prognostic model using the original cohort of cases from East Anglia with updated survival time in order to take into account age at diagnosis and to smooth out the survival function for tumour size and node status. Methods Multivariable Cox regression models were used to fit separate models for ER negative and ER positive disease. Continuous variables were fitted using fractional polynomials and a smoothed baseline hazard was obtained by regressing the baseline cumulative hazard for each patients against time using fractional polynomials. The fit of the prognostic models were then tested in three independent data sets that had also been used to validate the original version of PREDICT. Results In the model fitting data, after adjusting for other prognostic variables, there is an increase in risk of breast cancer specific mortality in younger and older patients with ER positive disease, with a substantial increase in risk for women diagnosed before the age of 35. In ER negative disease the risk increases slightly with age. The association between breast cancer specific mortality and both tumour size and number of positive nodes was non-linear with a more marked increase in risk with increasing size and increasing number of nodes in ER positive disease. The overall calibration and discrimination of the new version of PREDICT (v2) was good and comparable to that of the previous version in both model development and validation data sets. However, the calibration of v2 improved over v1 in patients diagnosed under the age of 40. Conclusions The PREDICT v2 is an improved prognostication and treatment benefit model compared with v1. The online version should continue to aid clinical decision making in women with early breast cancer.

SITE-Seq probes Cas9 cleavage sites in vitro and returns a comprehensive list of off-target sites at different Cas9–sgRNA concentrations. RNA-guided CRISPR–Cas9 endonucleases are widely used for genome engineering, but our understanding of Cas9 specificity remains incomplete. Here, we developed a biochemical method (SITE-Seq), using Cas9 programmed with single-guide RNAs (sgRNAs), to identify the sequence of cut sites within genomic DNA. Cells edited with the same Cas9–sgRNA complexes are then assayed for mutations at each cut site using amplicon sequencing. We used SITE-Seq to examine Cas9 specificity with sgRNAs targeting the human genome. The number of sites identified depended on sgRNA sequence and nuclease concentration. Sites identified at lower concentrations showed a higher propensity for off-target mutations in cells. The list of off-target sites showing activity in cells was influenced by sgRNP delivery, cell type and duration of exposure to the nuclease. Collectively, our results underscore the utility of combining comprehensive biochemical identification of off-target sites with independent cell-based measurements of activity at those sites when assessing nuclease activity and specificity.

Using data from a large-scale epidemiological sample (generously shared with us by the Norwegian Institute of Public Health), we provide initial examples of how and why such a stepped care and personalised health approach could be applied to address both the core features of autism and co-occurring conditions. Focused research strategies at the government or institutional level should be prioritised with an emphasis on clinical practice that can increase the understanding of what interventions work, for whom, when, how, with what general outcomes, and at what cost. Governments and services should monitor access to provision to ensure that underserved groups, including those who are minimally verbal, girls and women, minority ethnic groups, from socially disadvantaged backgrounds, or with severe co-occurring conditions, have equitable access to appropriate services. Societies in every part of the world have a duty of care to all people with autism and those who care for them, and investment in research and services needs to be targeted wisely to help them to reach better life outcomes and propel the change that makes this possible. Because it is defined by the intersection of social communication and sensory, restricted, and repetitive behaviours and interests, autism is a relatively specific disorder.

Cancer is a worldwide pandemic. The burden it imposes grows steadily on a global scale causing emotional, physical, and financial strains on individuals, families, and health care systems. Despite being the second leading cause of death worldwide, many cancers do not have screening programs and many people with a high risk of developing cancer fail to follow the advised medical screening regime due to the nature of the available screening tests and other challenges with compliance. Moreover, many liquid biopsy strategies being developed for early detection of cancer lack the sensitivity required to detect early-stage cancers. Early detection is key for improved quality of life, survival, and to reduce the financial burden of cancer treatments which are greater at later stage detection. This review examines the current liquid biopsy market, focusing in particular on the strengths and drawbacks of techniques in achieving early cancer detection. We explore the clinical utility of liquid biopsy technologies for the earlier detection of solid cancers, with a focus on how a combination of various spectroscopic and -omic methodologies may pave the way for more efficient cancer diagnostics.

Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a proinflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from induced pluripotent stem cell (iPSC) lines from patients with primary progressive multiple sclerosis (PPMS) failed to promote oligodendrocyte progenitor cell (OPC) maturation, whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2⁺ progenitor cells within white matter lesions of human progressiveMS (PMS) autopsy brain tissues and iPS-derived NPCs from patients with PPMS. Expression of cellular senescence genes in PPMS NPCs was found to be reversible by treatment with rapamycin, which then enhanced PPMS NPC support for oligodendrocyte (OL) differentiation. A proteomic analysis of the PPMS NPC secretome identified high-mobility group box-1 (HMGB1), which was found to be a senescence-associated inhibitor of OL differentiation. Transcriptome analysis of OPCs revealed that senescent NPCs induced expression of epigenetic regulators mediated by extracellular HMGB1. Lastly, we determined that progenitor cells are a source of elevated HMGB1 in human white matter lesions. Based on these data, we conclude that cellular senescence contributes to altered progenitor cell functions in demyelinated lesions in MS. Moreover, these data implicate cellular aging and senescence as a process that contributes to remyelination failure in PMS, which may impact how this disease is modeled and inform development of future myelin regeneration strategies.

Gambiense human African trypanosomiasis (gHAT), a neglected tropical disease caused by a parasite transmitted by tsetse flies, once inflicted over 30,000 annual cases and resulted in an estimated half a million deaths in the late twentieth century. An international gHAT control program has reduced cases to under 1,000 annually, encouraging the World Health Organization to target the elimination of gHAT transmission by 2030. This requires adopting innovative disease control approaches in foci where transmission persists. Since the last decade, case detection and treatment, the mainstay of controlling the disease, is supplemented by vector control using Tiny Targets, small insecticide-treated screens, which attract and kill tsetse. The advantages of Tiny Targets lie in their relatively low cost, easy deployment, and effectiveness. The Democratic Republic of Congo (DRC), bearing 65% of the 799 gHAT cases reported globally in 2022, introduced Tiny Targets in 2015. This study estimates the annual cost of vector control using Tiny Targets in the health district of Yasa Bonga in the DRC and identifies the main cost drivers. Economic and financial costs, collected from the provider’s perspective, were used to estimate the average cost of tsetse control expressed as cost (i) per target used, (ii) per target deployed, (iii) per linear kilometre of river controlled, and (iv) per square kilometre protected by vector control. Sensitivity analyses were conducted on key parameters for results robustness. The estimated annual economic cost for protecting an area of 1,925 km 2 was 120,000 USD. This translates to 5.30 USD per target used each year, 11 USD per target deployed in the field, 573 USD per linear km treated, and 62 USD per km 2 protected. These costs in the DRC are comparable to those in other countries. The study provides valuable information for practitioners and policymakers making rational, evidence-based decisions to control gHAT.

All coronaviruses known to have recently emerged as human pathogens probably originated in bats 1 . Here we use a single experimental platform based on immunodeficient mice implanted with human lung tissue (hereafter, human lung-only mice (LoM)) to demonstrate the efficient in vivo replication of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as two endogenous SARS-like bat coronaviruses that show potential for emergence as human pathogens. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats contain endogenous coronaviruses that are capable of direct transmission to humans. Our detailed analysis of in vivo infection with SARS-CoV-2 in human lung tissue from LoM showed a predominant infection of human lung epithelial cells, including type-2 pneumocytes that are present in alveoli and ciliated airway cells. Acute infection with SARS-CoV-2 was highly cytopathic and induced a robust and sustained type-I interferon and inflammatory cytokine and chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for SARS-CoV-2 infection. Our results show that therapeutic and prophylactic administration of EIDD-2801—an oral broad-spectrum antiviral agent that is currently in phase II/III clinical trials—markedly inhibited SARS-CoV-2 replication in vivo, and thus has considerable potential for the prevention and treatment of COVID-19. Human and bat coronaviruses replicate efficiently in immunodeficient mice implanted with human lung tissue, and treatment or prophylaxis using EIDD-2801 in this model suggests that this oral antiviral agent may be effective in preventing COVID-19.