Cyclin A-CDK1 suppresses the expression of the CDK1 activator CDC25A to safeguard timely mitotic entry.

Cyclin A and CDC25A are both activators of cyclin-dependent kinases (CDKs): cyclin A acts as an activating subunit of CDKs and CDC25A a phosphatase of the inhibitory phosphorylation sites of the CDKs. In this study, we uncovered an inverse relationship between the two CDK activators. As cyclin A is an essential gene, we generated a conditional silencing cell line using a combination of CRISPR-Cas9 and degron-tagged cyclin A. Destruction of cyclin A promoted an acute accumulation of CDC25A. The increase of CDC25A after cyclin A depletion occurred throughout the cell cycle and was independent on cell cycle delay caused by cyclin A deficiency. Moreover, we determined that the inverse relationship with cyclin A was specific for CDC25A and not for other CDC25 family members or kinases that regulate the same sites in CDKs. Unexpectedly, the upregulation of CDC25A was mainly caused by an increase in transcriptional activity instead of a change in the stability of the protein. Reversing the accumulation of CDC25A severely delayed G2-M in cyclin A-depleted cells. Taken together, these data provide evidence of a compensatory mechanism involving CDC25A that ensures timely mitotic entry at different levels of cyclin A.

Iterative Design of Ionizable Lipids for Intramuscular mRNA Delivery.

Lipid nanoparticles (LNPs) are the most clinically advanced delivery vehicles for RNA and have enabled the development of RNA-based drugs such as the mRNA COVID-19 vaccines. Functional delivery of mRNA by an LNP greatly depends on the inclusion of an ionizable lipid, and small changes to these lipid structures can significantly improve delivery. However, the structure-function relationships between ionizable lipids and mRNA delivery are poorly understood, especially for LNPs administered intramuscularly. Here, we show that the iterative design of a novel series of ionizable lipids generates key structure-activity relationships and enables the optimization of chemically distinct lipids with efficacy that is on-par with the current state of the art. We find that the combination of ionizable lipids comprising an ethanolamine core and LNPs with an apparent pKa between 6.6 and 6.9 maximizes intramuscular mRNA delivery. Furthermore, we report a nonlinear relationship between the lipid-to-mRNA mass ratio and protein expression, suggesting that a critical mass ratio exists for LNPs and may depend on ionizable lipid structure. Our findings add to the mechanistic understanding of ionizable lipids and demonstrate that hydrogen bonding, ionization behavior, and lipid-to-mRNA mass ratio are key design parameters affecting intramuscular mRNA delivery. We validate these insights by applying them to the rational design of new ionizable lipids. Overall, our iterative design strategy efficiently generates potent ionizable lipids. This hypothesis-driven method reveals structure-activity relationships that lay the foundation for the optimization of ionizable lipids in future LNP-RNA drugs. We foresee that this design strategy can be extended to other optimization parameters beyond intramuscular expression.

Ionizable Lipid with Supramolecular Chemistry Features for RNA Delivery In Vivo.

Lipid nanoparticles (LNPs) and ribonucleic acid (RNA) technology are highly versatile tools that can be deployed for diagnostic, prophylactic, and therapeutic applications. In this report, supramolecular chemistry concepts are incorporated into the rational design of a new ionizable lipid, C3-K2-E14, for systemic administration. This lipid incorporates a cone-shaped structure intended to facilitate cell bilayer disruption, and three tertiary amines to improve RNA binding. Additionally, hydroxyl and amide motifs are incorporated to further enhance RNA binding and improve LNP stability. Optimization of messenger RNA (mRNA) and small interfering RNA (siRNA) formulation conditions and lipid ratios produce LNPs with favorable diameter (<150 nm), polydispersity index (<0.15), and RNA encapsulation efficiency (>90%), all of which are preserved after 2 months at 4 or 37 °C storage in ready-to-use liquid form. The lipid and formulated LNPs are well-tolerated in animals and show no deleterious material-induced effects. Furthermore, 1 week after intravenous LNP administration, fluorescent signal from tagged RNA payloads are not detected. To demonstrate the long-term treatment potential for chronic diseases, repeated dosing of C3-K2-E14 LNPs containing siRNA that silences the colony stimulating factor-1 (CSF-1) gene can modulate leukocyte populations in vivo, further highlighting utility.

Development and evaluation of safety and effectiveness of novel cancer screening tests for routine clinical use with applications to multicancer detection technologies.

Multicancer screening is a promising approach to improving the detection of preclinical disease, but current technologies have limited ability to identify precursor or early stage lesions, and approaches for developing the evidentiary chain are unclear. Frameworks to enable development and evaluation from discovery through evidence of clinical effectiveness are discussed.

Nicotine dependence of cigarette and heated tobacco users in Japan, 2019: a cross-sectional analysis of the JASTIS Study.

OBJECTIVES: Japan is currently the biggest market of heated tobacco products (HTPs) in the world. Little is known about nicotine dependence among HTP users. Thus, the objective was to assess the association of type of tobacco use and time-to-first-use, a marker of nicotine dependence. METHODS: A cross-sectional analysis of the 2019 data from an internet cohort study was conducted. The analytical sample consisted of 2147 current (≥1 day use in the past 30 days) HTP and/or conventional cigarette users, aged 25+ years. Marginal structural binomial regression was used to estimate nicotine dependence prevalence ratios (PRs) for each category of tobacco use (exclusive daily cigarette, exclusive HTP (≥1 day), dual HTP+daily cigarette, dual HTP+non-daily cigarette), relative to exclusive, non-daily cigarette smoking. RESULTS: Using a 5 min cut-off for time-to-first-use, the prevalence of nicotine dependence was higher among dual users of HTP and daily cigarettes (PR=1.38; 95% CI: 1.05 to 1.82) and exclusive, daily cigarette users (PR=1.48; 95% CI: 1.15 to 1.91), relative to exclusive, non-daily cigarette users. However, nicotine dependence among exclusive HTP users, and dual HTP+non-daily cigarette users, did not differ from that of exclusive, non-daily cigarette users. When using 15 and 30 min cut-offs, all types of users, including exclusive HTP, had higher levels of nicotine dependence relative to exclusive, non-daily cigarette users. CONCLUSIONS: Regardless of HTP use, daily cigarette users had higher prevalence of nicotine dependence compared with non-daily cigarette users. Exclusive HTP users had similar (or potentially higher) dependence compared with exclusive, non-daily cigarette users. Longitudinal studies are needed to interrogate the public health implications of growing HTP use worldwide.

Late preterm antenatal corticosteroids in singleton and twin gestations: a retrospective cohort study.

BACKGROUND: In 2016, the American College of Obstetricians and Gynecologists recommended antenatal corticosteroids in the late preterm period for women at risk for preterm delivery. Limited real-world evidence exists on neonatal outcomes, particularly for twin gestations, following the guideline change. The study objective is to determine the association of antenatal corticosteroids in late preterm singleton and twin pregnancies with respiratory complications and hypoglycemia in a real-world clinical setting. METHODS: This is a retrospective cohort study comprising late preterm deliveries (4,341 mother-child pairs) within the Mount Sinai Health System, 2012-2018. The exposure of interest is antenatal corticosteroid administration of betamethasone during pregnancy between 34 0/7 and 36 6/7 weeks. Our primary outcomes are neonatal respiratory complications and hypoglycemia. Multivariable logistic regression was used to estimate the association between antenatal corticosteroid exposure and these two outcomes. We stratified the study population by singleton gestations and twins to minimize the potential confounding from different obstetric management between the two groups. RESULTS: Among a total of 4,341 mother-child pairs (3,309 singleton and 1,032 twin mother-child pairs), 745 mothers received betamethasone, of which 40.94% (305/745) received the full course. Relative to no treatment, a full course of betamethasone was associated with reduced odds of respiratory complications (OR = 0.53, 95% CI:[0.31-0.85], p < 0.01) and increased odds of hypoglycemia (OR = 1.86, 95%CI:[1.34-2.56], p < 0.01) in singletons; however, the association with respiratory complications was not significant in twins (OR = 0.42, 95% CI:[0.11-1.23], p = 0.16), but was associated with increased odds of hypoglycemia (OR = 2.18, 95% CI:[1.12-4.10], p = 0.02). A partial course of betamethasone (relative to no treatment) was not significantly associated with any of the outcomes, other than respiratory complications in twins (OR = 0.34, 95% CI:[0.12-0.82], p = 0.02). CONCLUSIONS: Exposure to antenatal corticosteroids in singletons and twins is associated with increased odds of hypoglycemia. Among singletons, exposure to the full dosage (i.e. two doses) was associated with decreased odds of respiratory complications but this was only the case for partial dose among twins. Twin gestations were not studied by the Antenatal Late Preterm Steroids trial. Therefore, our study findings will contribute to the paucity of evidence on the benefit of antenatal corticosteroids in this group. Health systems should systematically monitor guideline implementations to improve patient outcomes.

Maladaptive coping with the infodemic and sleep disturbance in the COVID-19 pandemic.

COVID-19 is caused by a novel virus with an unknown aetiology. People across the globe are dealing with not only a health crisis but also an 'infodemic', a term coined by the World Health Organization to refer to the avalanche of contradictory information that is arousing widespread confusion and anxiety. This study aimed to examine the prevalence of anxiety and sleep disturbance at the early stage of the pandemic, and unveil the information coping process underlying differential susceptibility to COVID-19 infection anxiety and sleep disturbance. The participants were 1,270 adults (47% men, Mage  = 42.82) from the UK and US who completed initial (Time 1) and follow-up (Time 2) surveys from 16 to 22 March and 18 to 24 May 2020, respectively. The prevalence of probable clinically relevant anxiety was 61% and 45% at the first and second time points, and more than half of the participants in this anxiety group also reported mild to severe sleep disturbance. Moreover, 41% of the participants perceived themselves as not having enough COVID-19-related information and reported higher levels of COVID-19 infection anxiety and sleep disturbance over time than those who perceived themselves as having enough of such information. Moderated mediation analysis identified two groups who were more vulnerable to both psychological problems: high blunters who sought COVID-19-related information online more frequently and high monitors who sought such information offline less frequently. These findings highlight the importance of a good match between information coping style and strategy deployment in dealing with an infodemic surrounding a novel disease.

Smoking trends in Mexico, 2002-2016: before and after the ratification of the WHO's Framework Convention on Tobacco Control.

INTRODUCTION: Mexico was the first Latin American country to ratify the Framework Convention on Tobacco Control (FCTC) in 2004, after which it implemented some key FCTC policies (e.g., taxes, smoke-free, pictorial warnings and ad bans). This study assessed trends in the prevalence of current, daily and non-daily smoking in Mexico before and after the implementation of key FCTC policies. METHODS: Data were analysed from two comparable, nationally representative surveys (i.e., the National Survey on Addictions 2002, 2011 and 2016, and the Global Adult Tobacco Survey 2009 and 2015). The pooled sample comprised 100 302 persons aged 15-65 years. Changes in the prevalence of current, daily and non-daily smoking were assessed. RESULTS: From 2002 to 2016, the prevalence of current smoking fell 11% in relative terms (from 21.5% to 19.0%). The decrease was registered between 2002 and 2009, and after that, a slight increase was observed (from 16.5% in 2009 to 19% in 2016). The prevalence of daily smoking decreased by about 50% between 2002 and 2016 (from 13.5% to 7.0%) with most of the decrease occurring by 2009. Conversely, the prevalence of non-daily smoking increased by 35% between 2009 and 2016 (from 8.8% to 11.9%). CONCLUSIONS: Full implementation of the FCTC is necessary to further reduce smoking. Specific interventions may be needed to target non-daily smokers, who now comprise more than half of current smokers in Mexico.

Social Capital-Accrual, Escape-From-Self, and Time-Displacement Effects of Internet Use During the COVID-19 Stay-at-Home Period: Prospective, Quantitative Survey Study.

BACKGROUND: COVID-19 has spread like wildfire across the globe, prompting many governments to impose unprecedented stay-at-home orders to limit its transmission. During an extended stay-at-home period, individuals may engage in more online leisure activities. Internet use is a double-edged sword that may have both desirable and undesirable effects on psychological well-being, and this study sought to disentangle adaptive from maladaptive internet use amidst this unusual health crisis. OBJECTIVE: The objectives of this study were to assess the prevalence of probable depression during the COVID-19 stay-at-home period and to test three hypothesized risk reduction or risk elevation mechanisms, namely social capital-accrual, escape-from-self, and time-displacement effects. METHODS: This study took place from March to May 2020 at the early stage of the pandemic. The study adopted a prospective design, with an online survey administered to 573 UK and 474 US adult residents at two assessment points 2 months apart. RESULTS: The prevalence of moderate to severe depression was 36% (bootstrap bias-corrected and accelerated [BCa] 95% CI 33%-39%) at Time 1 (ie, initial time point) and 27% (bootstrap BCa 95% CI 25%-30%) at Time 2 (ie, follow-up time point). The results supported the social capital-accrual hypothesis by showing that the approach coping style was inversely associated with Time 2 depression through its positive associations with both social networking and perceived family support. The results also supported the escape-from-self hypothesis by revealing that the avoidant coping style was positively associated with Time 2 depression through its positive associations with both gaming and cyberbullying victimization, but the serial mediation model was no longer significant after Time 1 depression and some demographic risk factors had been controlled for. Finally, the results supported the time-displacement hypothesis by showing that gaming was positively associated with Time 2 depression through its inverse associations with social networking and perceived family support. CONCLUSIONS: During the extended stay-at-home period in the early stages of the COVID-19 pandemic, the prevalence of probable depression during the 2-month study period was high among the UK and US residents. Individuals with distinct coping styles may engage in different types of online leisure activities and perceive varying levels of social support, which are associated with risks of probable depression.

A brief report on the clinical trial on neural mobilization exercise for joint pain in patients with rheumatoid arthritis.

BACKGROUND: In rheumatoid arthritis (RA) synovitis, activation of synoviocytes and infiltration of adaptive immune cells leads to synovial hyperplasia and joint swelling. Under the elevated extra-neural pressure, free nerve endings release neuropeptides, calcitonin gene-related peptide, and substance P, thus promoting neurogenic inflammation. OBJECTIVE: This study aimed to assess the effect of therapeutic neural mobilization (NM) exercises targeting the nervous system on disease impact in RA patients. METHODS: A total of 21 RA patients were randomized into NM (n = 11) and control (n = 10) groups. NM group patients performed NM exercises targeting the median, musculocutaneous, femoral, and saphenous nerve, as well as the entire nervous system twice daily for 4-8 weeks. Control RA patients performed gentle joint mobilization exercises targeting the same joints. Primary outcome was the change in pre-/post-treatment score in the validated Rheumatoid Arthritis Impact of Disease (RAID). Secondary outcome was erythrocyte sedimentation rate (ESR). RESULTS: There were no significant differences between the groups at baseline. No adverse events were observed and compliance was over 90%. Post-treatment, favorable changes were observed in the NM group RAID score: -5.1 vs. -0.8; weighted RAID score: -0.79 vs. -0.15. ESR was reduced in the NM group, albeit non-significantly. Regarding the RAID score domains, the NM group demonstrated significant improvements in pain and coping. CONCLUSION: The current data indicate a beneficial effect of NM exercises on pain and self-efficacy in our RA patients. Larger clinical studies are warranted to determine the clinical effectiveness of NM as a treatment for pain for RA patients and simultaneously address immune and neuropeptide modulation through NM.

Health promotion via SMS improves hypertension knowledge for deaf South Africans.

BACKGROUND: Signing Deaf South Africans have limited access to health information. As a result, their knowledge about health is limited. Cell phone usage in South Africa is high. This study aimed to assess whether a short message service (SMS)-based health promotion campaign could improve Deaf people's knowledge of hypertension and healthy living. Additionally, the study aimed to assess the acceptability of using SMSs for health promotion targeting Deaf people. METHODS: A baseline questionnaire assessed participants' knowledge about hypertension before an SMS-based information campaign was conducted. After the campaign, an exit questionnaire was conducted, containing the same questions as the baseline questionnaire with additional questions about general acceptability and communication preferences. Results were compared between baseline and exit, using McNemar's test, paired t-test and Wilcoxon signed-rank test. Focus groups aimed to get further information on the impact and acceptability of SMSs. The focus groups were analysed using inductive thematic analysis. RESULTS: The campaign recruited 82 participants for the baseline survey, but due to significant loss-to-follow-up and exclusions only 41 participants were included in the analysis of the survey. The majority (60%) were men. Eighty percent were employed, while 98% had not finished high school. The campaign showed a statistically significant improvement in overall knowledge about hypertension and healthy living amongst participants. Six individual questions out of 19 also showed a statistically significant improvement. Despite this, participants in focus groups found the medical terminology difficult to understand. Several ways of improving SMS campaigns for the Deaf were identified. These included using using pictures, using 'signed' SMSs, combining SMSs with signed drama and linking SMS-campaigns to an interactive communication service that would enable the Deaf to pose questions for clarification. Focus groups suggested that participants who were hypertensive during the campaign adopted a healthier lifestyle. CONCLUSION: SMSs were effective in improving Deaf people's knowledge of hypertension and healthy living. However, SMS-campaigns should be cognizant of Deaf people's unique needs and communication preference and explore how to accommodate these. TRIAL REGISTRATION: The research was registered with the Pan African Clinical Trial Registry on December 1, 2015. Identification number: PACTR201512001353476 .

Cp*Rh(iii)-catalyzed electrophilic amination of arylboronic acids with azo compounds for synthesis of arylhydrazides.

A [Cp*Rh(iii)]-catalyzed electrophilic amination of arylboronic acids with diethyl azodicarboxylate (DEAD) was developed, and arylhydrazides were produced in excellent yields and selectivity. The analogous amination with the arylazocarboxylates afforded the corresponding N,N-diarylhydrazides. The electrophilic amination of arylboronic acids with azocarboxylates proceeds readily under mild conditions with excellent functional group tolerance. Up to 99% yields were obtained. Preliminary mechanistic studies revealed that prior formation of an arylrhodium(iii) intermediate for the azo coupling reaction can be ruled out.

Investigating the relationship between self-rated health and social capital in South Africa: a multilevel panel data analysis.

BACKGROUND: The relationship between social capital and self-rated health has been documented in many developed compared to developing countries. Because social capital and health play important roles in development, it may be valuable to study their relationship in the context of a developing country with poorer health status. Further, the role of social capital research for health policy has not received much attention. This paper therefore examines the relationship between social capital and health in South Africa, a country with the history of colonialism and apartheid that has contributed to the social disintegration and destruction of social capital. METHODS: This study uses data from the National Income Dynamics Study (NIDS), the first nationally representative panel study in South Africa. Two waves of the NIDS were used in this paper--Wave 1 (2008) and Wave 2 (2010). Self-rated health, social capital (individual- and contextual-level), and other covariates related to the social determinants of health (SDH) were obtained from the NIDS. Individual-level social capital included group participation, personalised trust and generalised trust while contextual-level or neighbourhood-level social capital was obtained by aggregating from the individual-level and household-level social capital variables to the neighbourhood. Mixed effects models were fitted to predict self-rated health in Wave 2, using lagged covariates (from Wave 1). RESULTS: Individual personalised trust, individual community service group membership and neighbourhood personalised trust were beneficial to self-rated health. Reciprocity, associational activity and other types of group memberships were not found to be significantly associated with self-rated health in South Africa. Results indicate that both individual- and contextual-level social capital are associated with self-rated health. CONCLUSION: Policy makers may want to consider policies that impact socioeconomic conditions as well as social capital. Some of these policies are linked to the SDH. We contend that the significant social capital including community service membership can be encouraged through policy in a way that is in line with the values of the people. This is likely to impact on health and quality of life generally and lead to a reduction in the burden of disease in South Africa considering the historic context of the country.

Antenatal health promotion via short message service at a Midwife Obstetrics Unit in South Africa: a mixed methods study.

BACKGROUND: Adequate antenatal care is important to both the health of a pregnant woman and her unborn baby. Given South Africa's high rate of cellphone penetration, mobile health interventions have been touted as a potentially powerful means to disseminate health information. This study aimed to increase antenatal health knowledge and awareness by disseminating text messages about clinic procedures at antenatal visits, and how to be healthy during pregnancy. METHODS: Participants recruited were pregnant women attending a primary health care facility in Cape Town. A controlled clinical trial was carried out where the intervention group (n = 102) received text messages staggered according to the week of pregnancy at the time of recruitment. The control group (n = 104) received no text messages. These text messages contained antenatal health information, and were delivered in English, Xhosa or Afrikaans, according to the preference of each participant. A baseline knowledge questionnaire with nine questions was administered prior to the intervention. The same questionnaire was used with added health-related behaviour questions for the intervention group at exit. A modified intention-to-treat analysis was done. To compare the control and intervention group's knowledge, Fisher's exact tests and two-sample t-tests tests were carried out for binary and continuous outcomes, respectively. A focus group of seven participants from the intervention group was then conducted to gain more insight into how the text messages were perceived. RESULTS: There was substantial loss to follow-up during the study with only 57% of the participants retained at exit. No statistically significant difference was detected between the control and intervention group in any of the nine knowledge questions at exit (all p > 0.05). Responses from the focus group indicated that the text messages acted as a welcome reminder and a source of positive motivation, and were perceived as extended care from the health care provider. CONCLUSIONS: While the intervention failed to improve antenatal health knowledge, evidence from self-reported behaviour and the focus group suggests that text messages have the potential to motivate change in health-seeking behaviour. One should be mindful of loss to follow-up when rolling out mobile health interventions in developing country settings. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201406000841188. Registered 3 June 2014.

Bias due to coarsening of time intervals in the inference for the effectiveness of colorectal cancer screening.

BACKGROUND: Observational studies are frequently used to estimate the comparative effectiveness of different colorectal cancer (CRC) screening methods due to the practical limitations and time needed to conduct large clinical trials. However, time-varying confounders, e.g. polyp detection in the last screening, can bias statistical results. Recently, generalized methods, or G-methods, have been used for the analysis of observational studies of CRC screening, given their ability to account for such time-varying confounders. Discretization, or the process of converting continuous functions into discrete counterparts, is required for G-methods when the treatment and outcomes are assessed at a continuous scale. DEVELOPMENT: This paper evaluates the interplay between time-varying confounding and discretization, which can induce bias in assessing screening effectiveness. We investigate this bias in evaluating the effect of different CRC screening methods that differ from each other in typical screening frequency. APPLICATION: First, using theory, we establish the direction of the bias. Then, we use simulations of hypothetical settings to study the bias magnitude for varying levels of discretization, frequency of screening and length of the study period. We develop a method to assess possible bias due to coarsening in simulated situations. CONCLUSIONS: The proposed method can inform future studies of screening effectiveness, especially for CRC, by determining the choice of interval lengths where data are discretized to minimize bias due to coarsening while balancing computational costs.

Improving Knowledge About Pregnancy for Deaf South African Women of Reproductive Age Through a Text Messaging-Based Information Campaign: Mixed Methods Study.

BACKGROUND: Signing Deaf South Africans have limited access to health information and, consequently, limited knowledge about health. Maternal and neonatal mortality rates are high. Cell phone use is high, making it a potentially effective way of communicating about maternal and child health. OBJECTIVE: The primary aim of this study was to assess whether an SMS text messaging-based health information campaign could improve knowledge about pregnancy, antenatal care, and healthy living during pregnancy for signing Deaf South African women of reproductive age. The secondary aim was to evaluate the acceptability of such an intervention. METHODS: This study was designed as a pretest-posttest study. A baseline questionnaire assessed participants' knowledge about pregnancy, antenatal care, and healthy living during pregnancy before an SMS text messaging-based information campaign was conducted. After the campaign, an exit questionnaire was administered containing the same questions as the baseline questionnaire with additional questions on general acceptability and communication preferences. The results were compared between baseline and exit using the McNemar and Wilcoxon signed rank tests. A focus group aimed to obtain further information on the impact and acceptability of SMS text messages. The focus group was analyzed inductively. RESULTS: The study showed a statistically significant improvement in overall health knowledge among participants. Despite this, some participants found the medical terminology challenging to understand. Several ways of improving SMS text messaging campaigns for the Deaf were identified, including using Multimedia Messaging Services with a person signing messages and linking information campaigns to a communication service that would enable Deaf people to pose questions. The focus group also suggested that SMS text messages might play a role in motivating healthy behaviors during pregnancy. CONCLUSIONS: The SMS text messaging campaign effectively improved Deaf women's knowledge about pregnancy, antenatal care, and healthy living during pregnancy and has the potential to affect health behavior. This contrasts with a similar study on hearing pregnant women. This suggests that SMS text messages may be particularly effective in improving Deaf people's health knowledge. However, attention should be paid to Deaf participants' specific needs and communication preferences to optimize impact. The potential of using SMS text messaging campaigns to affect behavior should be studied. TRIAL REGISTRATION: Pan-African Clinical Trials Registry (PACTR) PACTR201512001352180; https://tinyurl.com/3rxvsrbe.

ALDH2 polymorphism, alcohol intake and the attributable burden of cancer in East Asia: systematic review, meta-analysis, and modeling study.

PURPOSE: To estimate the burden of alcohol-attributable cancer in East Asian populations accounting for aldehyde dehydrogenase-2 (ALDH2) genotype-specific cancer risk and alcohol exposure. METHODS: We conducted a systematic review and meta-analysis of eight databases on cancer risk to derive alcohol dose-response curves by ALDH2 genotype. A simulation-based approach using the Global Burden of Disease (GBD) modeling framework was applied to estimate the population attributable fraction, incidence, and disability-adjusted life-years (DALYs) lost to alcohol-attributable cancer. RESULTS: We included 34 studies (66,655 participants) from China, Japan, and South Korea in the meta-analysis. Alcohol dose-response curves for liver, esophageal, and oral cavity/pharynx cancer showed an increased risk for people with the inactivated ALDH2 genetic polymorphism, resulting in a higher burden of alcohol-attributable cancer compared to GBD estimates. Our methods estimated annual incidence of cancer of 230,177 cases, an underestimate of 69,596 cases compared to GBD estimates. Similarly, total DALYs lost annually were underestimated by 1.20 million. CONCLUSIONS: The burden of liver, esophageal, and oral cavity/pharynx cancer attributable to alcohol is underestimated in populations with the ALDH2 genetic polymorphism when compared to current estimates.

The tobacco quitline setting as a teachable moment: The Educating Quitline Users About Lung (EQUAL) cancer screening randomized trial.

Although lung cancer screening (LCS) using low-dose CT is recommended for high-risk individuals, screening adherence remains low. We conducted a randomized trial to compare two methods of providing LCS education to Maryland Tobacco Quitline (MTQ) callers in order to assess whether this setting may serve as a teachable moment for LCS-eligible individuals. MTQ callers (50-80 years, 20+ pack-years, prior LCS ≥12 months) completed the baseline and were randomized to the Print- or Web-based version of ShouldIScreen.com. Participants completed 1- and 4-month follow-up assessments to evaluate intervention engagement and LCS-related outcomes. Participants (Print = 152, Web = 146) were 61.7 (SD = 6.3) years old and reported 63.5 pack-years (SD = 36.0). Most identified as Black (54.2%), female (66.1%), having internet access (78.9%), completing other recommended cancer screenings (86.3%), and that they would undergo LCS if recommended by their provider (91.3%). By 4 months, significantly more Print (75.0%) than Web (61.6%) participants had read the materials (P = .01). Most reported the interventions contained "the right amount" of information (92.6%) and prepared them to talk with their doctor (57.2%). Regarding screening-related outcomes, 42.8% (Print) and 43.8% (Web) had scheduled or completed a low-dose CT scan or a shared decision-making visit (P = .86). In a racially diverse sample of LCS-eligible quitline callers, offering LCS educational materials resulted in high intervention engagement and screening-related appointments. As >20% did not have internet access, providing participants' preferred modality (web/print) may improve intervention engagement and knowledge. Improving LCS awareness represents an important opportunity to increase screening among eligible but unscreened quitline callers.

Although annual lung cancer screening (LCS) using low-dose CT is recommended for high-risk individuals, screening adherence remains low. In partnership with the Maryland Tobacco Quitline (MTQ), we compared Print (N = 152) versus Web (N = 146) methods for educating quitline callers about LCS. MTQ callers (50­80 years, 20+ pack-years) completed the baseline and the 1- and 4-month follow-up assessments to evaluate intervention engagement and LCS-related outcomes. Over half of participants identified as Black (54.4%), female (66.2%), and reported having internet access (78.9%), completing other recommended cancer screenings (86%), and would undergo LCS if recommended by their provider (91%). Significantly more Print (75.0%) than Web (61.9%) participants read the materials. Half of participants reported the interventions prepared them to talk with their doctor (57.4%). Regarding screening-related outcomes, 42.8% (Print) and 43.8% (Web) had scheduled or completed a CT scan or a shared decision-making visit. In a racially diverse sample of LCS-eligible quitline callers, offering LCS educational materials resulted in high intervention engagement and screening-related appointments. As >20% did not have internet access, offering the preferred intervention modality may result in improved intervention engagement and knowledge. Effectively improving awareness represents an opportunity to increase screening among LCS-eligible quitline callers.

Who is pregnant? Defining real-world data-based pregnancy episodes in the National COVID Cohort Collaborative (N3C).

Objectives: To define pregnancy episodes and estimate gestational age within electronic health record (EHR) data from the National COVID Cohort Collaborative (N3C). Materials and Methods: We developed a comprehensive approach, named Hierarchy and rule-based pregnancy episode Inference integrated with Pregnancy Progression Signatures (HIPPS), and applied it to EHR data in the N3C (January 1, 2018-April 7, 2022). HIPPS combines: (1) an extension of a previously published pregnancy episode algorithm, (2) a novel algorithm to detect gestational age-specific signatures of a progressing pregnancy for further episode support, and (3) pregnancy start date inference. Clinicians performed validation of HIPPS on a subset of episodes. We then generated pregnancy cohorts based on gestational age precision and pregnancy outcomes for assessment of accuracy and comparison of COVID-19 and other characteristics. Results: We identified 628 165 pregnant persons with 816 471 pregnancy episodes, of which 52.3% were live births, 24.4% were other outcomes (stillbirth, ectopic pregnancy, abortions), and 23.3% had unknown outcomes. Clinician validation agreed 98.8% with HIPPS-identified episodes. We were able to estimate start dates within 1 week of precision for 475 433 (58.2%) episodes. 62 540 (7.7%) episodes had incident COVID-19 during pregnancy. Discussion: HIPPS provides measures of support for pregnancy-related variables such as gestational age and pregnancy outcomes based on N3C data. Gestational age precision allows researchers to find time to events with reasonable confidence. Conclusion: We have developed a novel and robust approach for inferring pregnancy episodes and gestational age that addresses data inconsistency and missingness in EHR data.