A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(G4C2)exp in c9ALS/FTD via the nuclear RNA exosome.

A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(G4C2)exp, causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(G4C2)exp and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models. These studies reveal a mode of action whereby a small molecule diminishes intron retention caused by the r(G4C2)exp and allows the liberated intron to be eliminated by the nuclear RNA exosome, a multi-subunit degradation complex. Our findings highlight the complexity of mechanisms available to RNA-binding small molecules to alleviate disease pathologies and establishes a pipeline for the design of brain penetrant small molecules targeting RNA with novel modes of action in vivo.

Development and validation of the Trust in Multidimensional Healthcare Systems Scale (TIMHSS).

CONTEXT: The COVID-19 pandemic has reignited a commitment from the health policy and health services research communities to rebuilding trust in healthcare and created a renewed appetite for measures of trust for system monitoring and evaluation. The aim of the present paper was to develop a multidimensional measure of trust in healthcare that: (1) Is responsive to the conceptual and methodological limitations of existing measures; (2) Can be used to identify systemic explanations for lower levels of trust in equity-deserving populations; (3) Can be used to design and evaluate interventions aiming to (re)build trust. METHODS: We conducted a 2021 review of existing measures of trust in healthcare, 72 qualitative interviews (Aug-Dec 2021; oversampling for equity-deserving populations), an expert review consensus process (Oct 2021), and factor analyses and validation testing based on two waves of survey data (Nov 2021, n = 694; Jan-Feb 2022, n = 740 respectively). FINDINGS: We present the Trust in Multidimensional Healthcare Systems Scale (TIMHSS); a 38-item correlated three-factor measure of trust in doctors, policies, and the system. Measurement of invariance tests suggest that the TIMHSS can also be reliably administered to diverse populations. CONCLUSIONS: This global measure of trust in healthcare can be used to measure trust over time at a population level, or used within specific subpopulations, to inform interventions to (re)build trust. It can also be used within a clinical setting to provide a stronger evidence base for associations between trust and therapeutic outcomes.

Attitudes, subjective norms and perceived behavioural control factors influencing Canadian secondary school students' milk and milk alternatives consumption.

OBJECTIVE: The research objectives were to evaluate factors that influence Canadian secondary school students' milk and milk alternatives (MMA) consumption and to explore associations through age and gender lenses. DESIGN: A qualitative design was used, consisting of semi-structured interviews and photo-elicitation methods. Analysis was guided by the Theory of Planned Behaviour (TPB). Deductive and inductive thematic analyses were used to generate themes, charting data based on attributes such as gender and age. SETTING: Interviews were held virtually or via telephone. PARTICIPANTS: Participants were twenty-eight high school students from Ontario, Canada, diverse in terms of gender and age. RESULTS: Both desirable and undesirable beliefs about the health outcomes of consuming MMA were commonly discussed. These included health benefits such as strong bones, muscular strength, and growth, and health consequences like unwanted skin conditions, weight gain, and diseases. While boys and girls associated MMA consumption with muscular strength, boys predominantly considered this favourable, while girls discussed outcomes like unwanted skin conditions and weight gain more often. Adolescents' perspectives on taste/perceived enjoyment, environmentally friendly choices and animal welfare also influenced their MMA preferences. Parental influences were most cited among social factors, which appeared to be stronger during early adolescence. Factors involving cost, time and accessibility affected adolescents' beliefs about how difficult it was to consume MMA. CONCLUSIONS: Recommendations for shifting attitudes towards MMA are provided to address unfavourable beliefs towards these products. Interventions to increase MMA consumption among adolescents should include parents and address cost barriers.

Evaluating the effects of shelter-in-place policies during the COVID-19 pandemic.

We estimate the effects of shelter-in-place (SIP) orders during the first wave of the COVID-19 pandemic. We do not find detectable effects of these policies on disease spread or deaths. We find small but measurable effects on mobility that dissipate over time. And we find small, delayed effects on unemployment. We conduct additional analyses that separately assess the effects of expanding versus withdrawing SIP orders and test whether there are spillover effects in other states. Our results are consistent with prior studies showing that SIP orders have accounted for a relatively small share of the mobility trends and economic disruptions associated with the pandemic. We reanalyze two prior studies purporting to show that SIP orders caused large reductions in disease prevalence, and show that those results are not reliable. Our results do not imply that social distancing behavior by individuals, as distinct from SIP policy, is ineffective.

Phytonanotherapy for the Treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease, is a steatotic liver disease associated with metabolic syndrome (MetS), especially obesity, hypertension, diabetes, hyperlipidemia, and hypertriglyceridemia. MASLD in 43-44% of patients can progress to metabolic dysfunction-associated steatohepatitis (MASH), and 7-30% of these cases will progress to liver scarring (cirrhosis). To date, the mechanism of MASLD and its progression is not completely understood and there were no therapeutic strategies specifically tailored for MASLD/MASH until March 2024. The conventional antiobesity and antidiabetic pharmacological approaches used to reduce the progression of MASLD demonstrated favorable peripheral outcomes but insignificant effects on liver histology. Alternatively, phyto-synthesized metal-based nanoparticles (MNPs) are now being explored in the treatment of various liver diseases due to their unique bioactivities and reduced bystander effects. Although phytonanotherapy has not been explored in the clinical treatment of MASLD/MASH, MNPs such as gold NPs (AuNPs) and silver NPs (AgNPs) have been reported to improve metabolic processes by reducing blood glucose levels, body fat, and inflammation. Therefore, these actions suggest that MNPs can potentially be used in the treatment of MASLD/MASH and related metabolic diseases. Further studies are warranted to investigate the feasibility and efficacy of phytonanomedicine before clinical application.

The Cytotoxicity of Cotyledon orbiculata Aqueous Extract and the Biogenic Silver Nanoparticles Derived from the Extract.

Green synthesized silver nanoparticles (AgNPs) have become popular because of their promising biological activities. However, for most of these nanoparticles, the cytotoxic effects have not been determined and their safety is not guaranteed. In a previous study, we successfully synthesized AgNPs (Cotyledon-AgNPs) using an extract of Cotyledon orbiculata, a medicinal plant traditionally used in South Africa to treat skin conditions. Cotyledon-AgNPs were shown to have significant antimicrobial and wound-healing activities. Fibroblast cells treated with extracts of C. orbiculata and Cotyledon-AgNPs demonstrated an enhanced growth rate, which is essential in wound healing. These nanoparticles therefore have promising wound-healing activities. However, the cytotoxicity of these nanoparticles is not known. In this study, the toxic effects of C. orbiculata extract and Cotyledon-AgNPs on the non-cancerous skin fibroblast (KMST-6) were determined using in vitro assays to assess oxidative stress and cell death. Both the C. orbiculata extract and the Cotyledon-AgNPs did not show any significant cytotoxic effects in these assays. Gene expression analysis was also used to assess the cytotoxic effects of Cotyledon-AgNPs at a molecular level. Of the eighty-four molecular toxicity genes analysed, only eight (FASN, SREBF1, CPT2, ASB1, HSPA1B, ABCC2, CASP9, and MKI67) were differentially expressed. These genes are mainly involved in fatty acid and mitochondrial energy metabolism. The results support the finding that Cotyledon-AgNPs have low cytotoxicity at the concentrations tested. The upregulation of genes such as FASN, SERBF1, and MKI-67 also support previous findings that Cotyledon-AgNPs can promote wound healing via cell growth and proliferation. It can therefore be concluded that Cotyledon-AgNPs are not toxic to skin fibroblast cells at the concentration that promotes wound healing. These nanoparticles could possibly be safely used for wound healing.

Informing efforts beyond tailored promotional campaigns by understanding contextual factors shaping vaccine hesitancy among equity-deserving populations in Canada: an exploratory qualitative study.

BACKGROUND: Vaccine hesitancy exists on a continuum ranging between complete adherence and complete refusal due to doubts or concerns within a heterogeneous group of individuals. Despite widespread acknowledgement of the contextual factors influencing attitudes and beliefs shaping COVID-19 vaccine hesitancy, qualitative research with equity-deserving groups, accounting for unique lived experiences, remains a gap in the literature. We aim to identify and begin to understand and document the unique contextual factors shaping hesitancy by equity-deserving groups as it relates to relationships with government and health authorities. METHODS: Participants were recruited and interviewed between Aug-Dec 2021. Semi-structured interviews using a convergent interviewing technique were conducted with individuals from the general population, as well as individuals who identify as First Nations, Métis, or Inuit, members of the LGBT2SQ + community, low-income Canadians, Black Canadians, and newcomers. Interviews were audio recorded and transcribed by a team of researchers. Memos were written following interviews and used to complement the thematic analysis of the interview data. Themes are presented in the results section. RESULTS: The rationale for hesitancy among equity-deserving groups is consistent with literature documenting hesitancy in the general population. Contextual factors surrounding equity-deserving groups' attitudes and beliefs, however, are unique and relate to a history of oppression, discrimination, and genocide. We identified factors unique to subgroups; for example, religious or fatalistic beliefs among participant who identify as FNMI, fear associated with lack of testing and speed of vaccines' production among participants who identify as FNMI, Black, and LGBT2SQ + , distrust of the healthcare system for LGBT2SQ + and Black Canadians, and distrust of the government and opposition to vaccine mandates for participating who identify as LGBT2SQ + , low-income, FNMI, or Black Canadian. Newcomers stood out as very trusting of the government and accepting of COVID-19 vaccination. CONCLUSIONS: While our data on vaccine hesitancy largely mirror concerns reported in the vast body of literature citing rationale for COVID-19 hesitancy in high-income countries, the contextual factors identified in our work point to the need for wider systemic change. Our results may be used to support efforts, beyond tailored promotion campaigns, to support the confident acceptance of vaccines for COVID-19 and the acceptance of novel vaccines as future infectious diseases emerge.

Development and validation of the Trust in Government measure (TGM).

BACKGROUND: Trust in government is associated with health behaviours and is an important consideration in population health interventions. While there is a reported decline in public trust in government across OECD countries, the tools used to measure trust are limited in their use for informing action to (re)build trust, and have limitations related to reliability and validity. To address the limitations of existing measures available to track public trust, the aim of the present work was to develop a new measure of trust in government. METHODS: Fifty-six qualitative interviews (Aug-Oct 2021; oversampling for equity-deserving populations) were conducted to design a national survey, including factor analyses and validation testing (N = 878; June 1-14th 2022) in Canada. RESULTS: The measure demonstrated strong internal consistency (α = 0.96) and test validity (CFI = 0.96, RMSEA = 0.09, SRMR = 0.03), suggesting that trust in government can be measured as a single underlying construct. It also demonstrated strong criterion validity, as measured by significant (p < 0.0001) associations of scores with vaccine hesitancy, vaccine conspiracy beliefs, COVID-19 conspiracy beliefs, trust in public health messaging about COVID-19, and trust in public health advice about COVID-19. We present the Trust in Government Measure (TGM); a 13-item unidimensional measure of trust in Federal government. CONCLUSIONS: This measure can be used within high-income countries, particularly member countries within the OECD already in support of using tools to collect, publish and compare statistics. Our measure should be used by researchers and policy makers to measure trust in government as a key indicator of societal and public health.

Newcomer perceptions of COVID-19 countermeasures in Canada.

Newcomers to Canada have been disproportionally affected by COVID-19, with higher rates of infection and severity of illness. Determinants of higher rates may relate to social and structural inequities that impact newcomers' capacity to follow countermeasures. Our aim was to describe and document factors shaping newcomers' acceptance of COVID-19 countermeasures. Semi-structured qualitative interviews were conducted with individuals living in Canada for <5 years. Participants were asked to discuss their pandemic experiences, and perceptions and acceptance of measures. Five themes were identified: (i) belief in the necessity and efficacy of countermeasures; (ii) negative impact of measures on health/wellbeing; (iii) existing barriers to newcomer settlement exacerbated by pandemic measures; (iv) countermeasure adherence related to immigration status and (v) past experiences shaping countermeasure acceptance. Government should continue to provide messaging regarding the importance of measures for individual and population heath and continue to demonstrate a commitment to the interests of citizens. Importantly, newcomer trust in government should not be taken for granted, as this trust is critical for the acceptance of government interventions now and moving forward. It will be important to ensure that newcomers are given support to overcome challenges to settlement that were intensified during the pandemic.

Mental health interventions for immigrant-refugee children and youth living in Canada: a scoping review and way forward.

BACKGROUND: Traumatic life events experienced by immigrant-refugee children and youth may deteriorate their mental health and well-being. It is a public health priority to develop appropriate mental health interventions for this population. AIMS: To understand the psychosocial needs of immigrant-refugee children and youth resettled in Canada in the context of their school and community and to identify the characteristics of school-/community-based mental health programs for this group. METHOD: Arksey and O'Malley's methodology for scoping reviews was used to select the studies based on criteria, extract data in a table, and synthesize main findings. RESULTS: Fifteen peer-reviewed articles and five grey literature were identified. Key findings show that collaboration between schools, communities, and families play a crucial role in developing and implementing comprehensive mental health interventions for immigrant-refugee children/youth. Involving cultural brokers/interpreters and racially diverse school teachers/staff, is important to establish a trustful relationship between school authorities and marginalized population. CONCLUSIONS: Further research is needed to examine the impact of collaborative mental healthcare among multiracial and newcomer families in Canada. Furthermore, there is a need to study the impact of adopting creative expression programs at schools/communities to improve emotional/behavioural problems and enhance school performance of these groups.

DNA-Encoded Library Screening To Inform Design of a Ribonuclease Targeting Chimera (RiboTAC).

Ribonuclease targeting chimeras (RiboTACs) induce degradation of an RNA target by facilitating an interaction between an RNA and a ribonuclease (RNase). We describe the screening of a DNA-encoded library (DEL) to identify binders of monomeric RNase L to provide a compound that induced dimerization of RNase L, activating its ribonuclease activity. This compound was incorporated into the design of a next-generation RiboTAC that targeted the microRNA-21 (miR-21) precursor and alleviated a miR-21-associated cellular phenotype in triple-negative breast cancer cells. The RNA-binding module in the RiboTAC is Dovitinib, a known receptor tyrosine kinase (RTK) inhibitor, which was previously identified to bind miR-21 as an off-target. Conversion of Dovitinib into this RiboTAC reprograms the known drug to selectively affect the RNA target. This work demonstrates that DEL can be used to identify compounds that bind and recruit proteins with effector functions in heterobifunctional compounds.

Parents' perceptions on COVID-19 vaccination as the new routine for their children ≤ 11 years old.

Canadian children 5-11 years old became eligible for COVID-19 vaccination on November 19, 2021, with eligibility for younger children expected later. We aimed to descriptively assess parents' COVID-19 vaccine intentions and acceptability of future doses, including co-administration and annual vaccination for their children. We conducted a cross-sectional Canadian online survey of parents from October 14-November 12, 2021, just prior to authorization of the pediatric formulation of the BNT162b2 COVID-19 vaccine for children aged 5-11 years. We assessed parents' intention to vaccinate their children aged 5-11 years, 2-4 years, and 6-23 months; reasons for their intention; and preferences for delivery and access to vaccines. Of 1129 parents, 56% intended to vaccinate their child aged 5-11 years against COVID-19; intentions were lower for children aged 6-23 months (41.9%) and 2-4 years (45.4%). Most parents who intended to vaccinate supported co-administration with routine (61.1%) or influenza (55.4%) vaccines, administration at school (63.6%), receipt of booster doses of COVID-19 vaccine (57.8%), and annual vaccination (56.4%) for their child. Despite parents' high COVID-19 vaccination uptake for themselves (88.8%), intentions for children aged 5-11 years was low. Currently, 56.9% of Canadian children aged 5-11 years have received one dose of a COVID-19 vaccine, and only 37.1% are fully vaccinated. Given that intentions for children <5 years was lower than those 5-11 years, we can also expect low uptake in this group. Parents' preferences regarding delivery and access to COVID-19 vaccination should be considered by public health officials when planning vaccination strategies for children.

Perceived COVID-19 health and job risks faced by digital platform drivers and measures in place to protect them: A qualitative study.

INTRODUCTION: As they deliver food, packages, and people across cities, digital platform drivers (gig workers) are in a key position to become infected with COVID-19 and transmit it to many others. The aim of this study is to identify perceived COVID-19 exposure and job risks faced by workers and document the measures in place to protect their health, and how workers responded to these measures. METHODS: In 2020-2021, in-depth interviews were conducted in Ontario, Canada, with 33 digital platform drivers and managers across nine platforms that delivered food, packages, or people. Interviews focused on perceived COVID-19 risks and mitigation strategies. Audio recordings were transcribed verbatim and uploaded to NVivo software for coding by varied dual pairs of researchers. A Stakeholder Advisory Committee played an instrumental role in the study. RESULTS: As self-employed workers were without the protection of employment and occupational health standards, platform workers absorbed most of the occupational risks related to COVID-19. Despite safety measures (e.g., contactless delivery) and financial support for COVID-19 illnesses introduced by platform companies, perceived COVID-19 risks remained high because of platform-related work pressures, including rating systems. We identify five key COVID-19 related risks faced by the digital platform drivers. CONCLUSION: We situate platform drivers within the broad context of precarious employment and recommend organizational- and government-level interventions to prevent digital platform worker COVID-19 risks and to assist workers ill with COVID-19. Measures to protect the health of platform workers would benefit public health aims by reducing transmission by drivers to families, customers, and consequently, the greater population.

Place of alcohol in the 'wellness toolkits' of midlife women in different social classes: A qualitative study in South Australia.

In this article, we explore how women in different social classes had differential access to resources and services to enhance their 'wellness'-resulting in classed roles in alcohol consumption. We analyse data from a qualitative study on alcohol by midlife women in South Australia and employ the analogy of a 'toolkit' in order to understand the structural patterning of 'wellness tools'. Bourdieu's relational model of class guides our exploration of women's inequitable opportunities for wellness. Higher social class women had 'choices' facilitated by bulging wellness toolkits, such as yoga, exercise and healthy eating regimens-alcohol consumption was not essential to promoting 'wellness' and did not have an important place in their toolkits. Middle-class women had less well-stocked toolkits and consumed alcohol in a 'compensation approach' with other wellness tools. Alcohol consumption received positive recognition and was a legitimised form of enjoyment, fun and socialising, which needed counterbalancing with healthy activities. Working-class women had sparse toolkits-other than alcohol-which was a tool for dealing with life's difficulties. Their focus was less on 'promoting wellness' and more on 'managing challenging circumstances'. Our social class-based analysis is nestled within the sociology of consumption and sociological critiques of the wellness industry.

'I have a healthy relationship with alcohol': Australian midlife women, alcohol consumption and social class.

Alcohol consumption by Australian women during midlife has been increasing. Health promotion efforts to reduce alcohol consumption in order to reduce alcohol-related disease risk compete with the social contexts and value of alcohol in women's lives. This paper draws on 50 qualitative interviews with midlife women (45-64 years of age) from different social classes living in South Australia in order to gain an understanding of how and why women might justify their relationships with alcohol. Social class shaped and characterized the different types of relationships with alcohol available to women, structuring their logic for consuming alcohol and their ability to consider reducing (or 'breaking up with') alcohol. We identified more agentic relationships with alcohol in the narratives of affluent women. We identified a tendency for less control over alcohol-related decisions in the narratives of women with less privileged life chances, suggesting greater challenges in changing drinking patterns. If classed differences are not attended to in health promotion efforts, this might mitigate the effectiveness of alcohol risk messaging to women.

Benefits and harms of patient stories on social media from the perspective of healthcare providers and administrators in Ontario.

There has been a growing use of social media by patients to share their healthcare experiences and produce information that can be helpful to other patients seeking healthcare services. These stories can reveal issues in healthcare quality. However, faced with the inherent risks of social media, healthcare providers have been skeptical about the value of these stories, and many healthcare systems have adopted restrictive and protective policies to control the use of social media by healthcare providers. This study explores healthcare providers' and administrators' perspectives on patient stories on social media and whether they can use the stories to evaluate healthcare experiences. Semi-structured interviews (n = 21) were conducted with healthcare providers and administrators, including physicians, nurses, and quality managers in Ontario, Canada, between April 2018 and May 2019. Inductive and data-driven thematic analysis was used to analyze the data. Several barriers prevent healthcare providers from realizing the benefits of social media, including concerns about the quality of patients' feedback, the professional codes of conduct, and the time and effort required to process these stories. The study findings suggest that cultural changes in the healthcare system might be required to foster the use of social media for healthcare quality improvement and enable the development of a safe patient-provider communication environment that facilitates the exchange of constructive feedback between the two parties without the fear of legal consequences, breaches of patient privacy, or violation of professional codes of conduct.

The Antioxidant and In Vitro Wound Healing Activity of Cotyledon orbiculata Aqueous Extract and the Synthesized Biogenic Silver Nanoparticles.

The synthesis of silver nanoparticles using biogenic methods, particularly plants, has led to the discovery of several effective nanoparticles. In many instances, plant-derived silver nanoparticles have been shown to have more activity than the plant extract which was used to synthesize the nanoparticles. Silver nanoparticles have been successfully synthesized using the medicinal plant, Cotyledon orbiculata. This is a shrub found in the Western Cape province of South Africa. It has a long history of use in traditional medicine in the treatment of wounds and skin infections. The C. orbiculata synthesized silver nanoparticles (Cotyledon-AgNPs) were reported to have good antimicrobial and anti-inflammatory activities; however, their wound-healing properties have not been determined. This study aimed to determine the wound healing activity of Cotyledon-AgNPs using the scratch assay. Gene expression studies were also done to determine the nanoparticles' mechanism of action. The Cotyledon-AgNPs showed good antioxidant, growth-promoting and cell migration properties. Gene expression studies showed that the C. orbiculata water extract and Cotyledon-AgNPs promoted wound healing by upregulating genes involved in cell proliferation, migration and growth while downregulating pro-inflammatory genes. This confirms, for the first time that a water extract of C. orbiculata and silver nanoparticles synthesized from this extract are good wound-healing agents.

Broad Spectrum Anti-Bacterial Activity and Non-Selective Toxicity of Gum Arabic Silver Nanoparticles.

Silver nanoparticles (AgNPs) are the most commercialized nanomaterials and presumed to be biocompatible based on the biological effects of the bulk material. However, their physico-chemical properties differ significantly to the bulk materials and are associated with unique biological properties. The study investigated the antimicrobial and cytotoxicity effects of AgNPs synthesized using gum arabic (GA), sodium borohydride (NaBH4), and their combination as reducing agents. The AgNPs were characterized using ultraviolet-visible spectrophotometry (UV-Vis), dynamic light scattering (DLS), transmission electron microscopy (TEM), and Fourier-transform infrared spectroscopy (FT-IR). The anti-bacterial activity was assessed using agar well diffusion and microdilution assays, and the cytotoxicity effects on Caco-2, HT-29 and KMST-6 cells using MTT assay. The GA-synthesized AgNPs (GA-AgNPs) demonstrated higher bactericidal activity against all bacteria, and non-selective cytotoxicity towards normal and cancer cells. AgNPs reduced by NaBH4 (C-AgNPs) and the combination of GA and NaBH4 (GAC-AgNPs) had insignificant anti-bacterial activity and cytotoxicity at ≥50 µg/mL. The study showed that despite the notion that AgNPs are safe and biocompatible, their toxicity cannot be overruled and that their toxicity can be channeled by using biocompatible polymers, thereby providing a therapeutic window at concentrations that are least harmful to mammalian cells but toxic to bacteria.

Four Questions Nurses Can Ask to Predict PTSD 1 Year After a Motor Vehicle Crash.

BACKGROUND: The role of nurses in screening for posttraumatic stress disorder is crucial in trauma units. OBJECTIVES: To create and evaluate an easy and brief tool for nurses to predict chronic posttraumatic stress disorder 1 year after a motor vehicle crash. METHODS: We performed a 1-year follow-up multicenter study from 2007 to 2015, including 274 patients injured in a motor vehicle crash who were hospitalized in an orthopedic trauma unit. Nurses administered the DEPITAC questionnaire. Posttraumatic stress disorder was measured by the Post-Traumatic Stress Disorder Checklist of symptoms during the first year following the crash. A multivariable logistic regression model was implemented to select items significantly associated with posttraumatic stress disorder to improve the DEPITAC questionnaire. Predictive performance to predict posttraumatic stress disorder 1 year after the motor vehicle crash was examined for these different models. RESULTS: Of 274 patients studied, a total of 75.9% completed the questionnaire at 1 year of follow-up. We found that only two questions and two simple elements of the patient's medical record (other injury or a person dying during the crash, perception of vital threat, number of children, and length of stay in trauma) predicted posttraumatic stress disorder 1 year after a motor vehicle crash. CONCLUSIONS: The brevity of this evaluation, simple scoring rules, and screening test performance suggest that this new screening tool can be easily administered in the acute care setting by nurses.

Reprogramming of Protein-Targeted Small-Molecule Medicines to RNA by Ribonuclease Recruitment.

Reprogramming known medicines for a novel target with activity and selectivity over the canonical target is challenging. By studying the binding interactions between RNA folds and known small-molecule medicines and mining the resultant dataset across human RNAs, we identified that Dovitinib, a receptor tyrosine kinase (RTK) inhibitor, binds the precursor to microRNA-21 (pre-miR-21). Dovitinib was rationally reprogrammed for pre-miR-21 by using it as an RNA recognition element in a chimeric compound that also recruits RNase L to induce the RNA's catalytic degradation. By enhancing the inherent RNA-targeting activity and decreasing potency against canonical RTK protein targets in cells, the chimera shifted selectivity for pre-miR-21 by 2500-fold, alleviating disease progression in mouse models of triple-negative breast cancer and Alport Syndrome, both caused by miR-21 overexpression. Thus, targeted degradation can dramatically improve selectivity even across different biomolecules, i.e., protein versus RNA.