Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans.

In virtually all eukaryotes, the mitochondrial DNA (mtDNA) encodes proteins necessary for oxidative phosphorylation (OXPHOS) and RNAs required for their synthesis. The mechanisms of regulation of mtDNA copy number and expression are not completely understood but crucially ensure the correct stoichiometric assembly of OXPHOS complexes from nuclear- and mtDNA-encoded subunits. Here, we detect adenosine N6-methylation (6mA) on the mtDNA of diverse animal and plant species. This modification is regulated in C. elegans by the DNA methyltransferase DAMT-1 and demethylase ALKB-1. Misregulation of mtDNA 6mA through targeted modulation of these activities inappropriately alters mtDNA copy number and transcript levels, impairing OXPHOS function, elevating oxidative stress, and shortening lifespan. Compounding these defects, mtDNA 6mA hypomethylation promotes the cross-generational propagation of a deleterious mtDNA. Together, these results reveal that mtDNA 6mA is highly conserved among eukaryotes and regulates lifespan by influencing mtDNA copy number, expression, and heritable mutation levels in vivo.

A long way from Frome: improving connections between patients, local services and communities to reduce emergency admissions.

BACKGROUND: Low socio-economic status can lead to poor patient outcomes, exacerbated by lack of integration between health and social care and there is a demand for developing new models of working. AIM: To improve connections between patients, local services and their communities to reduce unscheduled admissions. DESIGN AND SETTING: A primary care cluster with areas of high deprivation, consisting of 11 general practices serving over 74,000 people. METHOD: A multi-disciplinary team with representatives from healthcare, local council and the third sector was formed to provide support for people with complex or social needs. A discharge liaison hub contacted patients following hospital discharge offering support, while cluster pharmacists led medicine reviews. Wellbeing Connectors were commissioned to act as a link to local wellbeing and social resources. Advance Care Planning was implemented to support personalised decision making. RESULTS: Unscheduled admissions in the over 75 age group decreased following the changes, equating to over 800 avoided monthly referrals to assessment units for the cluster. Over 2,500 patients have been reviewed by the MDT since its inception with referrals to social prescribing groups, physiotherapy and mental health teams; these patients are 20% less likely to contact their GP after their case is discussed. An improved sense of wellbeing was reported by 80% of patients supported by wellbeing connectors. Staff feel better able to meet patient needs and reported an increased joy in working. CONCLUSION: Improved integration between health, social care and third sector has led to a reduction in admissions, improved patient wellbeing and has improved job satisfaction amongst staff.

Time spent on active learning activities does not necessarily correlate with student exam performance: a controlled case study.

Active learning, including student thinking and discussion in class, has been shown to increase student learning gains. However, it is less clear how instructor-level variation in the implementation and timing of active learning activities affects student gains. Our study aims to investigate the extent to which the time spent on individual episodes of active learning activities influences student performance. We hypothesized that instructors who let students spend more time on peer discussion and individual thinking on practice problems associated with particular learning objectives would have better student exam scores on exam questions addressing those objectives. To test this hypothesis, we obtained a large data set of classroom recordings and student exam scores from an introductory biology course at a large 4-year university, where three instructors shared identical teaching materials and exams for different course offerings. Contrary to our hypothesis, although the three instructors spent significantly different amounts of time on episodes of thinking and peer discussion, there was no correlation between the total time spent on active learning activities and student performance on exam questions. Linear mixed-effects modeling of the effect of the length of episodes of student thinking and discussion on exam score found that in the context of shared instructional materials, the amount of course time spent on active learning activities did not reliably predict student performance on associated exam questions. This result held true even when only considering learning objectives with high variations in performance between offerings, difficult exam questions, or exam questions requiring higher-order thinking skills. Although our study was only conducted in one course, our results imply that time spent per individual episode of student thinking or peer discussion may not be the primary factor explaining the positive effects of active learning and that it may be worthwhile to explore other factors.

Defining documentation burden (DocBurden) and excess DocBurden for all health professionals: A scoping review.

OBJECTIVE: Efforts to reduce documentation burden (DocBurden) for all health professionals (HP) are aligned with national initiatives to improve clinician wellness and patient safety. Yet DocBurden has not been precisely defined, limiting national conversations and rigorous, reproducible, and meaningful measures. Increasing attention to DocBurden motivated this work to establish a standard definition of DocBurden, with the emergence of excessive DocBurden as a term. METHODS: We conducted a scoping review of DocBurden definitions and descriptions, searching six databases for scholarly, peer-reviewed, and gray literature sources, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extensions for Scoping Review (PRISMA-ScR) guidance. For the concept clarification phase of work, we used the American Nursing Informatics Association (ANIA)'s 6-Domains of Burden Framework. RESULTS: A total of 153 articles were included based on a priori criteria. Most articles described a focus on DocBurden, but only 18% (n=28) provided a definition. We define excessive DocBurden as the stress and unnecessarily heavy work a HP or healthcare team experiences when usability of documentation systems and documentation activities (i.e., generation, review, analysis and synthesis of patient data) are not aligned in support of care delivery. A negative connotation was attached to burden without a neutral state in included sources, which does not align with dictionary definitions of burden. CONCLUSIONS: Existing literature does not distinguish between a baseline or required task load to conduct patient care resulting from usability issues(DocBurden), and the unnecessarily heavy tasks and requirements that contribute to excessive DocBurden. Our definition of excessive DocBurden explicitly acknowledges this distinction, to support development of meaningful measures for understanding and intervening on excessive DocBurden locally, nationally and internationally.

The clinical utility of a glaucoma polygenic risk score in four population-based European-ancestry cohorts.

OBJECTIVE: We used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts. DESIGN: Secondary analysis of four prospective population-based studies. PARTICIPANTS: We included four European-ancestry cohorts: the United States (US) based Nurses' Health Study (NHS), NHS2, and the Health Professionals Follow-up Study, and the Rotterdam Study (RS) in the Netherlands. The US cohorts included female nurses and male health professionals aged 55+ years. The RS included residents aged 45 years or older living in Rotterdam, the Netherlands. METHODS: PRS weights were estimated by applying the Lassosum method on imputed genotype and phenotype data from the UK-Biobank. This resulted in 144,020 variants, single nucleotide polymorphism (SNPs) and indels, with non-zero betas that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models' concordance (Harrell's C-statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits. MAIN OUTCOME MEASURES: The relative risk for POAG and Harrell's C-statistic (the equivalent of an area-under-the-curve for longitudinal models). RESULTS: Among 1,046 cases and 38,809‬ controls, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08, 5.18) in the US cohorts, and 4.89 (2.93, 8.17) in the Rotterdam Study, compared with participants with median genetic risk (3rd quintile). In restricted cubic spline analyses, the relation between continuous PRS and POAG risk increased exponentially in the US and Rotterdam cohorts (Pspline<0.05). Combining age, sex, intraocular pressure >25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (0.73, 0.75). Adding the PRS to this model improved the concordance to 0.82 (0.80, 0.84). In a meta-analysis of all cohorts, cases in the highest tertile had a larger cup-disc ratio at diagnosis, by 0.11 (0.07, 0.15), and a 2.07-fold increased risk of requiring glaucoma surgery (1.19, 3.60). CONCLUSIONS: Incorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies.

Comparing barriers to early stage diagnosis of hepatocellular carcinoma between safety net hospitals and academic medical centers: An analysis from the United States Safety-Net Collaborative.

BACKGROUND AND OBJECTIVES: Early detection of hepatocellular carcinoma (HCC) is associated with improved survival. However, a greater proportion of patients treated at safety net hospitals (SNHs) present with late-stage disease compared to those at academic medical centers (AMCs). This study aims to identify barriers to diagnosis of HCC, highlighting differences between SNHs and AMCs. METHODS: The US Safety Net Collaborative-HCC database was queried. Patients were stratified by facility of diagnosis (SNH or AMC). Patient demographics and HCC screening rates were examined. The primary outcome was stage at diagnosis (AJCC I/II-"early"; AJCC III/IV-"late"). RESULTS: 1290 patients were included; 50.2% diagnosed at SNHs and 49.8% at AMCs. At SNHs, 44.4% of patients were diagnosed late, compared to 27.6% at AMCs. On multivariable regression, Black race was associated with late diagnosis in both facilities (SNH: odds ratio 1.96, p = 0.03; AMC: 2.27, <0.01). Screening was associated with decreased odds of late diagnosis (SNH: 0.46, p = 0.04; AMC: 0.37, p < 0.01). CONCLUSIONS: Black race was associated with late diagnosis of HCC, while screening was associated with early diagnosis across institutional types. These results suggest socially constructed racial bias in screening and diagnosis of HCC. Screening efforts targeting SNH patients and Black patients at all facilities are essential to reduce disparities.

Newborn screening analytes and structural birth defects among 27,000 newborns.

BACKGROUND: Emerging evidence suggests newborn screening analytes may yield insights into the etiologies of birth defects, yet no effort has evaluated associations between a range of newborn screening analytes and birth defects. METHODS: This population-based study pooled statewide data on birth defects, birth certificates, and newborn screening analytes from Texas occurring between January 1, 2007 and December 31, 2009. Associations between a panel of thirty-six newborn screening analytes, collected by the statewide Texas Newborn Screening Program, and the presence of a birth defect, defined as at least one of 39 birth defects diagnoses recorded by the Texas Birth Defects Registry, were assessed using regression analysis. FINDINGS: Of the 27,643 births identified, 20,205 had at least one of the 39 birth defects of interest (cases) as identified by the Texas Birth Defects Registry, while 7,438 did not have a birth defect (controls). Among 1,404 analyte-birth defect associations evaluated, 377 were significant in replication analysis. Analytes most consistently associated with birth defects included the phenylalanine/tyrosine ratio (N = 29 birth defects), tyrosine (N = 28 birth defects), and thyroxine (N = 25 birth defects). Birth defects most frequently associated with a range of analytes included gastroschisis (N = 29 analytes), several cardiovascular defects (N = 26 analytes), and spina bifida (N = 23 analytes). CONCLUSIONS: Several significant and novel associations were observed between newborn screening analytes and birth defects. While some findings could be consequences of the defects themselves or to the care provided to infants with these defects, these findings could help to elucidate mechanisms underlying the etiology of some birth defects.

CDC's Laboratory Activities to Support Newborn Screening for Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) was added to the HHS Secretary's Recommended Uniform Screening Panel for newborn screening (NBS) in 2018, enabling early diagnosis and treatment of impacted infants to prevent irreversible motor neuron damage. In anticipation of supporting SMA newborn screening, scientists at the U.S. Centers for Disease Control and Prevention (CDC) have worked towards building resources for public health laboratories in four phases since 2013. In Phase 1, CDC established a real-time PCR assay, which uses a locked nucleic acid probe to attain the needed specificity, to detect SMN1 exon 7. In Phase 2, we developed quality assurance dried blood spot materials made with transduced lymphoblast cell lines established from de-identified SMA patients, carriers, and unaffected donors. In 2021, CDC implemented Phase 3, a proficiency testing program, that now supports 115 NBS labs around the world. We are currently completing Phase 4, which includes the implementation of an external SMA quality control material program. Also, during this time, CDC has provided individual technical assistance to NBS programs and bench training to NBS scientists during our annual molecular workshop. These CDC-led activities have contributed to the rapid and full implementation of SMA screening in all 50 U.S. states as of February 2024.

Maternal Placental Growth Factor (PlGF) levels, sonographic placental parameters, and outcomes of IVF pregnancies with and without embryo trophectoderm biopsy.

PURPOSE: In vitro fertilization (IVF) is associated with abnormal trophoblast invasion and resultant decreased levels of circulating placental biomarkers such as placental growth factor (PlGF). Our objective was to evaluate maternal serum levels of second/third trimester PlGF, sonographic placental parameters, and clinical outcomes among IVF frozen embryo transfer (FET) pregnancies with and without embryo trophectoderm biopsy. METHODS: This was a retrospective study of pregnant patients who conceived using a single frozen embryo transfer (FET) and gave birth between 30 January 2018 and 31 May 2021. We compared PlGF levels, sonographic placental parameters, and clinical outcomes between FET with biopsy and FET without biopsy groups. RESULTS: The median PlGF level was 614.5 pg/mL (IQR 406-1020) for FET pregnancies with biopsy, and 717.0 pg/mL (IQR 552-1215) for FET pregnancies without biopsy. The adjusted mean difference was 190.9 pg/mL lower in the FET biopsy group (95% CI, -410.6, 28.8; p = 0.088). There were no statistically significant differences in placental parameters or clinical pregnancy outcomes. CONCLUSION: This exploratory study demonstrated a possible trend toward lower maternal serum PlGF in the pregnancies conceived with FET using a biopsied embryo. Further investigation is warranted into the potential placental health effects of trophectoderm biopsy.

A feature-specific prediction error model explains dopaminergic heterogeneity.

The hypothesis that midbrain dopamine (DA) neurons broadcast a reward prediction error (RPE) is among the great successes of computational neuroscience. However, recent results contradict a core aspect of this theory: specifically that the neurons convey a scalar, homogeneous signal. While the predominant family of extensions to the RPE model replicates the classic model in multiple parallel circuits, we argue that these models are ill suited to explain reports of heterogeneity in task variable encoding across DA neurons. Instead, we introduce a complementary 'feature-specific RPE' model, positing that individual ventral tegmental area DA neurons report RPEs for different aspects of an animal's moment-to-moment situation. Further, we show how our framework can be extended to explain patterns of heterogeneity in action responses reported among substantia nigra pars compacta DA neurons. This theory reconciles new observations of DA heterogeneity with classic ideas about RPE coding while also providing a new perspective of how the brain performs reinforcement learning in high-dimensional environments.

Risks of Placental Abruption and Preterm Delivery in Patients Undergoing Assisted Reproduction.

Importance: Patients using assisted reproductive technology (ART) may need additional counseling about the increased risks of placental abruption and preterm delivery. Further investigation into the potential additive risk of ART and placental abruption is needed. Objective: To ascertain the risk of placental abruption in patients who conceived with ART and to evaluate if placental abruption and ART conception are associated with an increased risk of preterm delivery (<37 weeks' gestation) over and above the risks conferred by each factor alone. Design, Setting, and Participants: This cross-sectional study used data from the National Inpatient Sample, which includes data from all-payer hospital inpatient discharges from 48 states across the US. Participants included women aged 15 to 54 years who delivered from 2000 through 2019. Data were analyzed from January 17 to April 18, 2024. Exposures: Pregnancies conceived with ART. Main Outcomes and Measures: Risks of placental abruption and preterm delivery in ART conception compared with spontaneous conceptions. Associations were expressed as odds ratios (ORs) and 95% CIs derived from weighted logistic regression models before and after adjusting for confounders. The relative excess risk due to interaction (RERI) of the risk of preterm delivery based on ART conception and placental abruption was also assessed. Results: Of 78 901 058 deliveries, the mean (SD) maternal age was 27.9 (6.0) years, and 9 212 117 patients (11.7%) were Black individuals, 14 878 539 (18.9%) were Hispanic individuals, 34 899 594 (44.2%) were White individuals, and 19 910 807 (25.2%) were individuals of other races and ethnicities. Of the total hospital deliveries, 98.2% were singleton pregnancies, 68.8% were vaginal deliveries, and 52.1% were covered by private insurance. The risks of placental abruption among spontaneous and ART conceptions were 11 and 17 per 1000 hospital discharges, respectively. After adjusting for confounders, the adjusted OR (AOR) of placental abruption was 1.42 (95% CI, 1.34-1.51) in ART pregnancies compared with spontaneous conceptions, with increased odds in White women (AOR, 1.42; 95% CI, 1.31-1.53) compared with Black women (AOR, 1.16; 95% CI, 0.93-1.44). The odds of preterm delivery were significantly higher in pregnancies conceived by ART compared with spontaneous conceptions (AOR, 1.46; 95% CI, 1.42-1.51). The risk of preterm delivery increased when patients had both ART conception and placental abruption (RERI, 2.0; 95% CI, 0.5-3.5). Conclusions and Relevance: In this cross-sectional study, patients who conceived using ART and developed placental abruption had a greater risk of preterm delivery compared with spontaneous conception without placental abruption. These findings have implications for counseling patients who seek infertility treatment and obstetrical management of ART pregnancies.

Multisite Pragmatic Cluster-Randomized Controlled Trial of the CONCERN Early Warning System.

Importance: Late predictions of hospitalized patient deterioration, resulting from early warning systems (EWS) with limited data sources and/or a care team's lack of shared situational awareness, contribute to delays in clinical interventions. The COmmunicating Narrative Concerns Entered by RNs (CONCERN) Early Warning System (EWS) uses real-time nursing surveillance documentation patterns in its machine learning algorithm to identify patients' deterioration risk up to 42 hours earlier than other EWSs. Objective: To test our a priori hypothesis that patients with care teams informed by the CONCERN EWS intervention have a lower mortality rate and shorter length of stay (LOS) than the patients with teams not informed by CONCERN EWS. Design: One-year multisite, pragmatic controlled clinical trial with cluster-randomization of acute and intensive care units to intervention or usual-care groups. Setting: Two large U.S. health systems. Participants: Adult patients admitted to acute and intensive care units, excluding those on hospice/palliative/comfort care, or with Do Not Resuscitate/Do Not Intubate orders. Intervention: The CONCERN EWS intervention calculates patient deterioration risk based on nurses' concern levels measured by surveillance documentation patterns, and it displays the categorical risk score (low, increased, high) in the electronic health record (EHR) for care team members. Main Outcomes and Measures: Primary outcomes: in-hospital mortality, LOS; survival analysis was used. Secondary outcomes: cardiopulmonary arrest, sepsis, unanticipated ICU transfers, 30-day hospital readmission. Results: A total of 60 893 hospital encounters (33 024 intervention and 27 869 usual-care) were included. Both groups had similar patient age, race, ethnicity, and illness severity distributions. Patients in the intervention group had a 35.6% decreased risk of death (adjusted hazard ratio [HR], 0.644; 95% confidence interval [CI], 0.532-0.778; P<.0001), 11.2% decreased LOS (adjusted incidence rate ratio, 0.914; 95% CI, 0.902-0.926; P<.0001), 7.5% decreased risk of sepsis (adjusted HR, 0.925; 95% CI, 0.861-0.993; P=.0317), and 24.9% increased risk of unanticipated ICU transfer (adjusted HR, 1.249; 95% CI, 1.093-1.426; P=.0011) compared with patients in the usual-care group. Conclusions and Relevance: A hospital-wide EWS based on nursing surveillance patterns decreased in-hospital mortality, sepsis, and LOS when integrated into the care team's EHR workflow. Trial Registration: ClinicalTrials.gov Identifier: NCT03911687.

COVID-19 vaccination before or during pregnancy results in high, sustained maternal neutralizing activity to SARS-CoV-2 wild-type and Delta/Omicron variants of concern, particularly following a booster dose or infection.

OBJECTIVES: To investigate multi-dose and timings of COVID-19 vaccines in preventing antenatal infection. DESIGN: Prospective observational study investigating primary vaccinations, boosters, antenatal COVID-19 infections, neutralizing antibody (Nab) durability, and cross-reactivity to Delta and Omicron variants of concern (VOCs). RESULTS: Ninety-eight patients completed primary vaccination prepregnancy (29.6%) and antenatally (63.3%), 24.2% of whom had antenatal COVID-19, while 7.1% were unvaccinated (28.6% had antenatal COVID-19). None had severe COVID-19. Prepregnancy vaccination resulted in vaccination-to-infection delay of 23.3 weeks, which extended to 45.2 weeks with a booster, compared to 16.9 weeks following antenatal vaccination (P < 0.001). Infections occurred at 26.2 weeks gestation in women vaccinated prepregnancy compared to 36.2 weeks gestation in those vaccinated during pregnancy (P < 0.007). The risk of COVID-19 infection was higher without antenatal vaccination (hazard ratio [HR] 14.6, P = 0.05) and after prepregnancy vaccination without a booster (HR 10.4, P = 0.002). Antenatal vaccinations initially led to high Nab levels, with mild waning but subsequent rebound. Significant Nab enhancement occurred with a third-trimester booster. Maternal-neonatal Nab transfer was efficient (transfer ratio >1), and cross-reactivity to VOCs was observed. CONCLUSION: Completing vaccination during any trimester delays COVID-19 infection and maintains effective neutralizing activity throughout pregnancy, with robust cross-reactivity to VOCs and efficient maternal-neonatal transfer.

Use of Diagnostic Codes for Primary Open-Angle Glaucoma Polygenic Risk Score Construction in Electronic Health Record-Linked Biobanks.

PURPOSE: Polygenic risk scores (PRSs) likely predict risk and prognosis of glaucoma. We compared the PRS performance for primary open-angle glaucoma (POAG), defined using International Classification of Diseases (ICD) codes vs manual medical record review. DESIGN: Retrospective cohort study. METHODS: We identified POAG cases in the Mount Sinai BioMe and Mass General Brigham (MGB) biobanks using ICD codes. We confirmed POAG based on optical coherence tomograms and visual fields. In a separate 5% sample, the absence of POAG was confirmed with intraocular pressure and cup-disc ratio criteria. We used genotype data and either self-reported glaucoma diagnoses or ICD-10 codes for glaucoma diagnoses from the UK Biobank and the lassosum method to compute a genome-wide POAG PRS. We compared the area under the curve (AUC) for POAG prediction based on ICD codes vs medical records. RESULTS: We reviewed 804 of 996 BioMe and 367 of 1006 MGB ICD-identified cases. In BioMe and MGB, respectively, positive predictive value was 53% and 55%; negative predictive value was 96% and 97%; sensitivity was 97% and 97%; and specificity was 44% and 53%. Adjusted PRS AUCs for POAG using ICD codes vs manual record review in BioMe were not statistically different (P ≥.21) by ancestry: 0.77 vs 0.75 for African, 0.80 vs 0.80 for Hispanic, and 0.81 vs 0.81 for European. Results were similar in MGB (P ≥.18): 0.72 vs 0.80 for African, 0.83 vs 0.86 for Hispanic, and 0.74 vs 0.73 for European. CONCLUSIONS: A POAG PRS performed similarly using either manual review or ICD codes in 2 electronic health record-linked biobanks; manual assessment of glaucoma status might not be necessary for some PRS studies. However, caution should be exercised when using ICD codes for glaucoma diagnosis given their low specificity (44%-53%) for manually confirmed cases of glaucoma.

A Cross Sectional Survey of Factors Related to Cannabis Use as a Sleep Aid Among Canadian Cancer Survivors.

OBJECTIVES: Poor sleep is a common side effect of cancer. Cannabis is increasingly used to manage cancer treatment-related symptoms, including sleep. This study investigated factors related to cannabis use for sleep among Canadian cancer survivors. METHOD: Adult Canadian cancer survivors (N = 940) were recruited via the Angus Reid Institute and completed an online, cross-sectional survey. Univariate and multiple binomial logistic regression models identified factors associated with cannabis use for sleep. RESULTS: Of the participants (Mage = 64.5 yrs; Women = 51.1%; White = 92.9%), 25.1% (n = 236) currently use cannabis for sleep. Participants were at greater odds of using cannabis for sleep if they identified as a gender other than man or woman (AOR = 11.132), were diagnosed with multiple medical conditions (2:AOR = 1.988; 3+:AOR = 1.902), two psychological conditions (AOR = 2.171), multiple sleep disorders (AOR = 2.338), insomnia (AOR = 1.942), bone (AOR = 6.535), gastrointestinal (AOR = 4.307), genitourinary (AOR = 2.586), hematological (AOR = 4.739), or an unlisted cancer (AOR = 3.470), received hormone therapy only (AOR = 3.054), drink heavily (AOR = 2.748), or had mild insomnia (AOR = 1.828). Older participants (AOR=.972) and those with sleep apnea were less likely to use cannabis for sleep (AOR=.560). CONCLUSION: Given its prevalence, research is needed to understand how factors associated with cannabis use as a sleep aid among Canadian cancer survivors may influence its use and effectiveness and whether these factors are barriers to accessing evidence-based treatments.

Understanding the Gap: A Cross-Sectional Survey of ELSI Scholars' Dissemination Practices and Translation Goals.

BACKGROUND: Researchers engaged in the study of the ethical, legal, and social implications (ELSI) of genetics and genomics are often publicly funded and intend their work to be in the public interest. These features of U.S. ELSI research create an imperative for these scholars to demonstrate the public utility of their work and the expectation that they engage in research that has potential to inform policy or practice outcomes. In support of the fulfillment of this "translational mandate," the Center for ELSI Resources and Analysis (CERA), funded by the National Human Genome Research Institute (NHGRI), aims to facilitate community-informed, ELSI research results synthesis and dissemination. However, little is known about how ELSI research scholars define the goals of translation and imagine the intended users of their research findings. METHODOLOGY: We distributed a Qualtrics survey to ELSI scholars that aimed to determine: (1) researchers' expectations for their research findings in relation to policy or practice outcomes, (2) the stakeholder groups researchers believe could benefit from their research findings, and (3) the methods researchers use to foster the uptake of their findings by those stakeholders. RESULTS: Most ELSI researchers surveyed thought there were stakeholders that could benefit from their research findings, including health care professionals, at-risk individuals, patients, and their family members, policy-makers, and researchers/scientists, and expected their research findings to inform the creation or revision of laws, policies, or practice guidelines. Most researchers planned to disseminate findings directly to relevant stakeholders, with fewer expecting dissemination support from research funders, universities, or other entities. CONCLUSION: The broad range of research topics, disciplines, and set of potential end users represented in ELSI reseach complicate the work of a knowledge broker. Nonetheless, the CERA can play an important role in disseminating ELSI results to relevant stakeholders. Further research should explore outreach mechanisms.

Cancer-associated DNA Hypermethylation of Polycomb Targets Requires DNMT3A Dual Recognition of Histone H2AK119 Ubiquitination and the Nucleosome Acidic Patch.

During tumor development, promoter CpG islands (CGIs) that are normally silenced by Polycomb repressive complexes (PRCs) become DNA hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) catalyze CpG methylation at PRC-regulated regions remains unclear. Here we report a cryo-EM structure of the DNMT3A long isoform (DNMT3A1) N-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine 119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 N-terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Furthermore, aberrant redistribution of DNMT3A1 to Polycomb target genes inhibits their transcriptional activation during cell differentiation and recapitulates the cancer-associated DNA hypermethylation signature. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for countering promoter CGI DNA hypermethylation, a major molecular hallmark of cancer.

Efficacy and Safety of Cell-based Immunotherapy in The Treatment of Recurrent or Metastatic Nasopharyngeal Carcinoma - A Systematic Review and Meta-analysis.

BACKGROUND: Recurrent/Metastatic Nasopharyngeal Carcinoma (RM-NPC) remains difficult to treat and contributes to considerable mortality. The first-line treatment for RM-NPC is Gemcitabine and Cisplatin and second-line treatment options differ. The endemic variant of NPC is associated with Epstein-Barr Virus (EBV). Therefore, Cell-based Immunotherapy (CBI) targeting EBV-specific RM-NPC may be effective. METHODS: We systematically searched PubMed, Embase and the Cochrane Library for randomised or observational studies investigating the efficacy and safety of CBI in the treatment of RM-NPC. We performed all meta-analyses using the random-effects model. Studies were further stratified by endemicity, nature of disease and drug type to investigate for potential between-study heterogeneity and additional pre-specified tests were employed to assess for publication bias. RESULTS: We screened 1,671 studies and included 13 studies with 403 participants in the systematic review, of which nine studies were eligible for meta-analysis. The use of CBI monotherapy as second or subsequent line treatment for EBV-positive RM-NPC revealed an ORR of 10 % (95 %CI = 3 %-29 %), median PFS of 2.37 months (95 %CI = 1.23-3.51) and median OS of 10.16 months (95 %CI = 0.67-19.65). For EBV-specific Cytotoxic T-Lymphocyte monotherapy, the pooled PD rate was 54 % (95 %CI = 9 %-93 %), SD rate was 22 % (95 %CI = 2 %-75 %) and incidence rate of any grade adverse events was 45 %. For Dendritic Cell monotherapy, a PD rate of 80 % (95 % CI = 29 %-98 %), SD rate of 11 % (95 % CI = 0 %-82 %) and incidence rate of any grade adverse events of 29 % was achieved. CONCLUSION: CBI monotherapy demonstrates some activity in pre-treated RM-NPC. More trials are needed to better understand how to integrate CBI into RM-NPC care.

How are people coping with working from home during the COVID-19 pandemic?: Experiences from the Netherlands and South Korea.

COVID-19 has made working from home routine for many. People who have had to maintain their productivity, particularly in physically and/or socially unacceptable home-working situations, experienced one of the pandemic's disadvantages. The experience can vary substantially among individuals as well as by country. This study presents the results of a comparative study of the Netherlands and Korea. Working from home was not uncommon in the Netherlands before the pandemic; however, in Korea, employers adopted working from home from its start, and that increased rapidly. An online survey enabled us to compare the physical and social conditions of current home workspaces in both countries, to understand how well-equipped they were to support people who had to work from home. We studied the changes in productivity and physical/mental health before and during COVID-19, to learn how people coped with working from home in both countries. Contrary to expectations, Koreans showed better scores than people in the Netherlands, in terms of changes in health and productivity. This article discusses various aspects of that result, such as satisfaction with home workspace, housing type, job position and prior experience, compulsoriness, and frequency of working from home. Relieving stress and concentration appeared to be the most important dimensions of telecommuters' satisfaction with working from home environments in both countries. The results are the basis for suggesting the development of strategies for a desirable WFH environment, considering different background contexts, experiences and cultures.

Improving care in lung cancer surgery: a review of quality measures and evolving standards.

PURPOSE OF REVIEW: Lung cancer is the leading cause of cancer-related death in the United States. Pulmonary resection, in addition to perioperative systemic therapies, is a cornerstone of treatment for operable patients with early-stage and locoregional disease. In recent years, increased emphasis has been placed on surgical quality metrics: specific and evidence-based structural, process, and outcome measures that aim to decrease variation in lung cancer care and improve long term outcomes. These metrics can be divided into potential areas of intervention or improvement in the preoperative, intraoperative, and postoperative phases of care and form the basis of guidelines issued by organizations including the National Cancer Center Network (NCCN) and Society of Thoracic Surgeons (STS). This review focuses on established quality metrics associated with lung cancer surgery with an emphasis on the most recent research and guidelines. RECENT FINDINGS: Over the past 18 months, quality metrics across the peri-operative care period were explored, including optimal invasive mediastinal staging preoperatively, the extent of intraoperative lymphadenectomy, surgical approaches related to minimally invasive resection, and enhanced recovery pathways that facilitate early discharge following pulmonary resection. SUMMARY: Quality metrics in lung cancer surgery is an exciting and important area of research. Adherence to quality metrics has been shown to improve overall survival and guidelines supporting their use allows targeted quality improvement efforts at a local level to facilitate more consistent, less variable oncologic outcomes across centers.