Evaluation of the first 5 years of the Next Generation GP leadership programme: balancing autonomy and accountability.

BACKGROUND: In 2017, a group of trainee general practitioners (GPs) came together to design and deliver a six-session leadership development programme for their peer trainee and early career GPs: the Next Generation GP programme. Over 2500 GPs took part in Next Generation GP between 2017 and 2022. AIM: To evaluate the origins and development of the Next Generation GP programme, its early impact on individuals and general practice, and what it reveals about GPs' needs for career and leadership development at a time of major workforce and demand pressures. METHODS: A rapid review of evidence on general practice workforce and career trends informed the design of qualitative research interviews (n=28) with a purposive sample of programme participants, primary care leaders and educational experts. This was supplemented by analysis of secondary data from participant evaluations of programme workshops. RESULTS: Many programme participants reported: improved competence in leadership skills, increased understanding of the health system, having new support networks and more energy for their GP role. Respondents pointed out the strengths of the programme, also highlighting ways in which it could be adapted to enable a transition to a more sustainable position within broader clinical and leadership career development. CONCLUSIONS: Next Generation GP has to date largely fulfilled its programme objectives. It now needs more tangible, longer-term objectives against which to assess outcomes. This evaluation has contributed to evidence about primary care leadership needing more policy attention, for the balance of autonomy and accountability within GP leadership needs careful and sustained support.

Classification Criteria for Axial Disease in Youth with Juvenile Spondyloarthritis.

OBJECTIVES: To develop and validate classification criteria for axial disease in youth with juvenile spondyloarthritis (SpA; AxJSpA). METHODS: This international initiative consisted of four phases: 1) Item generation; 2) Item reduction; 3) Criteria development; and 4) Validation of the AxJSpA criteria by an independent team of experts in an internationally representative Validation cohort. RESULTS: These criteria are intended to be used on youth with a physician diagnosis of juvenile SpA and for whom axial disease is suspected. Item generation consisted of a systematic literature review and a free-listing exercise using input from international physicians and collectively resulted in 108 items. After the item reduction exercise and expert panel input, 37 items remained for further consideration. The final AxJSpA criteria domains included: imaging: active inflammation, imaging: structural lesions, pain chronicity, pain pattern, pain location, stiffness, and genetics. The most heavily weighted domains were active inflammation and structural lesions on imaging. Imaging typical of sacroiliitis was deemed necessary, but not sufficient, to classify a youth with AxJSpA. The threshold for classification of AxJSpA was a score of ≥55 (out of 100). When tested in the validation data set, the final criteria had a specificity of 97.5% (95% CI: 91.4-99.7), sensitivity of 64.3% (95% CI: 54.9-73.1) and Area Under the Receiver Operating Characteristic (AUROC) curve of 0.81 (95% CI: 0.76-0.86). CONCLUSIONS: The new AxJSpA classification criteria require an entry criterion, physician diagnosis of juvenile SpA, and include seven weighted domains. The AxJSpA classification criteria are validated and designed to identify participants for research studies.

Service innovations for people with multiple long-term conditions: reflections of a rapid evaluation team.

Background: People living with multiple long-term conditions represent a significant concern for National Health Service policy and practice, and their care is a major theme in the 2019 National Health Service Long Term Plan. The Birmingham RAND and Cambridge Rapid Evaluation Centre team has undertaken a thematic synthesis of the 10 evaluations it has conducted from 2018 to 2023, exploring the needs, priorities and implications for people with multiple long-term conditions. Objectives: The aims for this overarching study were to: (1) build a body of learning about service innovations in primary and community settings for people of all ages with multiple long-term conditions, focused on questions that matter most to people with multimorbidity; and (2) develop methodological insights about how rapid evaluation can be used to inform the scoping, testing and implementation of service innovations for people with multiple long-term conditions. Design: The focus on multiple long-term conditions came from a Birmingham RAND and Cambridge Rapid Evaluation Centre prioritisation process undertaken in 2018 using James Lind Alliance methods. Cross-analysis of the findings from the 10 individual rapid evaluations was supplemented by (1) building aspects of multimorbidity into the design of later evaluations; (2) interviewing national and regional stakeholders (n=19) working in or alongside integrated care systems; (3) undertaking a rapid review of evidence on remote monitoring for people with multiple long-term conditions (19 papers included); and (4) testing overall insights with organisations representing patients and carers through a patient, public and professional engagement workshop with 10 participants plus members of the research team. Results: While living with multiple long-term conditions is common and is the norm for people over the age of 50 using health and care services, it is not often a focus of health service provision or innovation, nor of research and evaluation activity. We discuss six themes emerging from the totality of the study: (1) our health system is mainly organised around single conditions and not multiple long-term conditions; (2) research calls and studies usually focus on single conditions and associated services; (3) building opportunities for engaged, informed individuals and carers and improved self-management; (4) the importance of measures that matter for patients and carers; (5) barriers to developing and implementing service innovations for people with multiple long-term conditions; and (6) what is needed to make patients with multiple long-term conditions a priority in healthcare planning and delivery. Limitations: Care of people with multiple long-term conditions was not the principal focus of several of the rapid evaluations. While this was a finding in itself, it limited our learning about designing and implementing, as well as methodological approaches to evaluating, service innovations for people with multiple long-term conditions. Conclusions: Through a thematic analysis of the portfolio of evaluations, we have deduced a set of suggested implications for how the needs of people with multiple long-term conditions can be better embedded in policy, research and practice. Future work: Areas of uncertainty related to the care of people with multiple long-term conditions should be further explored, including developing and testing measures of patient experience of (un)co-ordinated care across settings, and interrogating the experience of health and care staff when working with people with multiple long-term conditions, to understand what works. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR134284) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 15. See the NIHR Funding and Awards website for further award information.

Many people in England live with two or more physical and/or mental health conditions that are expected to last for years. Estimates vary, but it is likely that a majority of National Health Service services are serving people living with two or more long-term conditions. We wanted to find out how well the needs of this group are taken into account when new types of health care are introduced, or existing services are reorganised. To do this, we went back to all 10 of the health service innovations that had been studied by our Birmingham RAND and Cambridge Evaluation Centre from 2018 to 2023. We did some extra research, including discussions with patient representatives and interviews with National Health Service policy-makers and managers at national and regional levels. We also looked at what new research had been published about one example of a new healthcare technology that is intended to help people who have several long-term health conditions: monitors that can be used by health service staff to measure patients' symptoms when they are in their own home. Our main finding was that most National Health Service attention is given to organising care for single conditions, often treating them in isolation. Patients' many treatments and needs are not routinely considered all at the same time by healthcare staff, nor by researchers. Care for one condition is too often not co-ordinated with care for other health problems that a patient may have. Although the situation of people living with several long-term health conditions is in principle understood by healthcare staff, managers and researchers, relatively little is done in practice to meet their needs. We conclude by suggesting ways that policy-makers, healthcare staff and researchers could improve how they help people living with multiple long-term conditions.

The impact of libraries and informationists on patient and population care: a mixed-methods study.

Objective: While several studies have examined the effectiveness of librarian interactions with clinicians and impact of librarians on patient care, no studies have explored a library's effects on population care. The goal of this study was to investigate the library's impact on both patient and population care. Methods: Using a sequential exploratory mixed-methods design, we first interviewed a small set of clinicians and researchers active in patient and population care. Based on the themes that we discovered through coding the interviews, we created a survey that was sent to faculty in the health sciences and the health system. Results: We collected data from a representative sample of our population. We discovered that all respondents value the library and informationists, using our services most for teaching, publishing, presenting, and professional development. Conclusion: We now have data to support our value to our population and to show where we can do more work to improve the use of our services. Our study shows the value of doing a mixed-methods sequential exploration in which themes that are important to our user community were identified prior to launching a large-scale survey.

Multiple Unfolded Protein Response pathways cooperate to link cytosolic dsDNA release to Stimulator of Interferon Gene (STING) activation.

The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to "sterile" endogenous threats and pathogens without nominal DNA or cyclic di-nucleotide stimuli. Previous work showed an endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR), activates STING. Herein, we sought to determine if ER stress generated a STING ligand, and to identify the UPR pathways involved. Induction of IFN-ß expression following stimulation with the UPR inducer thapsigargin (TPG) or oxygen glucose deprivation required both STING and the dsDNA-sensing cyclic GMP-AMP synthase (cGAS). Furthermore, TPG increased cytosolic mitochondrial DNA, and immunofluorescence visualized dsDNA punctae in murine and human cells, providing a cGAS stimulus. N-acetylcysteine decreased IFN-ß induction by TPG, implicating reactive oxygen species (ROS). However, mitoTEMPO, a mitochondrial oxidative stress inhibitor did not impact TPG-induced IFN. On the other hand, inhibiting the inositol requiring enzyme 1 (IRE1) ER stress sensor and its target transcription factor XBP1 decreased the generation of cytosolic dsDNA. iNOS upregulation was XBP1-dependent, and an iNOS inhibitor decreased cytosolic dsDNA and IFN-ß, implicating ROS downstream of the IRE1-XBP1 pathway. Inhibition of the PKR-like ER kinase (PERK) pathway also attenuated cytoplasmic dsDNA release. The PERK-regulated apoptotic factor Bim was required for both dsDNA release and IFN-ß mRNA induction. Finally, XBP1 and PERK pathways contributed to cytosolic dsDNA release and IFN-induction by the RNA virus, Vesicular Stomatitis Virus (VSV). Together, our findings suggest that ER stressors, including viral pathogens without nominal STING or cGAS ligands such as RNA viruses, trigger multiple canonical UPR pathways that cooperate to activate STING and downstream IFN-ß via mitochondrial dsDNA release.

Contextual Factors Relevant to Implementing Social Risk Factor Screening and Referrals in Cancer Survivorship: A Qualitative Study.

Introduction: Social risk factors such as food insecurity and lack of transportation can negatively affect health outcomes, yet implementation of screening and referral for social risk factors is limited in medical settings, particularly in cancer survivorship. Methods: We conducted 18 qualitative, semistructured interviews among oncology teams in 3 health systems in Washington, DC, during February and March 2022. We applied the Exploration, Preparation, Implementation, Sustainment Framework to develop a deductive codebook, performed thematic analysis on the interview transcripts, and summarized our results descriptively. Results: Health systems varied in clinical and support staff roles and capacity. None of the participating clinics had an electronic health record (EHR)-based process for identifying patients who completed their cancer treatment ("survivors") or a standardized cancer survivorship program. Their capacities also differed for documenting social risk factors and referrals in the EHR. Interviewees expressed awareness of the prevalence and effect of social risk factors on cancer survivors, but none employed a systematic process for identifying and addressing social risk factors. Recommendations for increasing screening for social risk factors included designating a person to fulfill this role, improving data tracking tools in the EHR, and creating systems to maintain up-to-date information and contacts for community-based organizations. Conclusion: The complexity of cancer care workflows and lack of reimbursement results in a limited ability for clinic staff members to screen and make referrals for social risk factors. Creating clinical workflows that are flexible and tailored to staffing realities may contribute to successful implementation of a screening and referral program. Improving ongoing communication with community-based organizations to address needs was deemed important by interviewees.

Persistence of Diffusion Capacity Impairment and Its Relationship with Dyspnea 12 Months after Hospitalization for COVID-19.

Background: Dyspnea is a common persistent symptom after acute coronavirus disease 2019 illness (COVID-19). One potential explanation for post-COVID-19 dyspnea is a reduction in diffusion capacity. This longitudinal study investigated diffusion capacity and its relationship with dyspnea on exertion in individuals previously hospitalized with COVID-19. Methods: Eligible participants had been hospitalized for the treatment of acute COVID-19 and were assessed at 6 weeks, 6 months, and 12 months after discharge. Pulmonary function testing, diffusion capacity of carbon monoxide (DLCO), blood gas analysis and the level of dyspnea (Borg scale; before and after a 6 min walk test [6 MWT]) were performed. Participants were divided into subgroups based on the presence or absence of dyspnea during the 6 MWT at 12 months after hospitalization. Results: Seventy-two participants (twenty-two female, mean age 59.8 ± 13.5 years) were included. At 12 months after discharge, 41/72 participants (57%) had DLCO below the lower limit of normal and 56/72 (78%) had DLCO < 80% of the predicted value. Individuals with exertional dyspnea had significantly lower DLCO than those without exertional dyspnea (p = 0.001). In participants with DLCO data being available at three timepoints over 12 months (baseline, 6 months, and 12 months) after discharge (n = 25), DLCO improved between 6 weeks and 6 months after hospital discharge, but not thereafter (p = 0.017). Conclusions: About 2/3 of the post-COVID individuals in this study had impaired diffusion capacity at 12 months after hospital discharge. There was an association between persisting dyspnea on exertion and significantly reduced DLCO. Impaired diffusion capacity improved over the first 6 months after hospitalization but not thereafter.

Older mothers and their difficult adult children: a life course exploration.

Adult child to parent violence is a growing international social problem that needs to be better understood to develop clinical interventions. An exploratory study on the antecedents of early life adversity on adult child to parent violence/elder mistreatment was carried out using secondary analysis. Directed content analysis was used based on life course theory with a data set of older mothers all > 57 years old (J. R. Smith 2021, 2022). Measurement of instances of child abuse, domestic violence, and birth trauma among abused older mothers was conducted. All the older women had reported being negatively affected by their adult children's problems and 56% reported being physically attacked. A case example is presented to illustrate how repeated incidents of abuse or neglect in early life might explain an older woman's inability to take actions for her own safety.

Use and effectiveness of the arts for enhancing healthcare students' empathy skills: A mixed methods systematic review.

OBJECTIVE: To identify, critically appraise and synthesise evidence of the use and effectiveness of the arts for enhancing pre-registration/prelicensure healthcare students' empathy skills. DESIGN: A systematic review of mixed methods literature. DATA SOURCES: A search of six electronic databases was conducted. REVIEW METHODS: Articles describing English language, peer-reviewed, primary research studies reporting empathy as an outcome of an arts-based intervention with pre-registration/prelicensure healthcare students (years 1-7) and published between 2000 and 2024 were eligible for inclusion. The JBI Manual for Evidence Synthesis guided the review and a convergent segregated methodology was used to synthesise the results. Methodological rigour of included studies was examined using the Mixed Methods Appraisal Tool. RESULTS: Twenty studies from 12 countries described the use of the arts to develop empathy, with visual arts being the most common approach (n = 8). Other modalities included film, drama, digital stories, literature, creative writing, music, poetry, photography and dance. Studies included nursing, medicine and dental, pharmacy and/or health sciences students. Ten studies used quantitative methods, three qualitative, and seven used mixed methods designs. Of the studies that presented pre-post outcome measures, nine reported significant gains in empathy scores at post-test and two reported non-significant gains in empathy. In eight studies, empathy scores demonstrated a significant intervention effect with effect sizes ranging from moderate (d = 0.52) to large (d = 1.19). Findings from qualitative studies revealed that arts pedagogies support students to better understand the perspectives of people with a lived experience of suffering but that these approaches are sometimes perceived negatively by students. CONCLUSIONS: Arts interventions generally have a positive effect on healthcare students' empathy levels and enable a nuanced conceptual understanding of empathy. Arts modalities used as a stimulus for active learning and supported with facilitated group-based discussion and/or reflection, tend to be most effective.

Multimorbidity clusters in adults 50 years or older with and without a history of cancer: National Health Interview Survey, 2018.

BACKGROUND: Multimorbidity is increasing among adults in the United States. Yet limited research has examined multimorbidity clusters in persons aged 50 years and older with and without a history of cancer. An increased understanding of multimorbidity clusters may improve the cancer survivorship experience for survivors with multimorbidity. METHODS: We identified 7580 adults aged 50 years and older with 2 or more diseases-including 811 adults with a history of primary breast, colorectal, cervical, prostate, or lung cancer-from the 2018 National Health Interview Survey. Exploratory factor analysis identified clusters of multimorbidity among cancer survivors and individuals without a history of cancer (controls). Frequency tables and chi-square tests were performed to determine overall differences in sociodemographic characteristics, health-related characteristics, and multimorbidity between groups. RESULTS: Cancer survivors reported a higher prevalence of having 4 or more diseases compared to controls (57% and 38%, respectively). Our analysis identified 6 clusters for cancer survivors and 4 clusters for controls. Three clusters (pulmonary, cardiac, and liver) included the same diseases for cancer survivors and controls. CONCLUSIONS: Diseases clustered differently across adults ≥ 50 years of age with and without a history of cancer. Findings from this study may be used to inform clinical care, increase the development and dissemination of multilevel public health interventions, escalate system improvements, and initiate innovative policy reform.

Rapid evaluation of service innovations in health and social care: key considerations.

Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (RSET: 16/138/17; BRACE: 16/138/31).

Pathogen-driven CRISPR screens identify TREX1 as a regulator of DNA self-sensing during influenza virus infection.

Host:pathogen interactions dictate the outcome of infection, yet the limitations of current approaches leave large regions of this interface unexplored. Here, we develop a novel fitness-based screen that queries factors important during the middle to late stages of infection. This is achieved by engineering influenza virus to direct the screen by programming dCas9 to modulate host gene expression. Our genome-wide screen for pro-viral factors identifies the cytoplasmic DNA exonuclease TREX1. TREX1 degrades cytoplasmic DNA to prevent inappropriate innate immune activation by self-DNA. We reveal that this same process aids influenza virus replication. Infection triggers release of mitochondrial DNA into the cytoplasm, activating antiviral signaling via cGAS and STING. TREX1 metabolizes the DNA, preventing its sensing. Collectively, these data show that self-DNA is deployed to amplify innate immunity, a process tempered by TREX1. Moreover, they demonstrate the power and generality of pathogen-driven fitness-based screens to pinpoint key host regulators of infection.

Leveraging twitter data to understand nurses' emotion dynamics during the COVID-19 pandemic.

The nursing workforce is the largest discipline in healthcare and has been at the forefront of the COVID-19 pandemic response since the outbreak of COVID-19. However, the impact of COVID-19 on the nursing workforce is largely unknown as is the emotional burden experienced by nurses throughout the different waves of the pandemic. Conventional approaches often use survey question-based instruments to learn nurses' emotions, and may not reflect actual everyday emotions but the beliefs specific to survey questions. Social media has been increasingly used to express people's thoughts and feelings. This paper uses Twitter data to describe the emotional dynamics of registered nurse and student nurse groups residing in New South Wales in Australia during the COVID-19 pandemic. A novel analysis framework that considered emotions, talking topics, the unfolding development of COVID-19, as well as government public health actions and significant events was utilised to detect the emotion dynamics of nurses and student nurses. The results found that the emotional dynamics of registered and student nurses were significantly correlated with the development of COVID-19 at different waves. Both groups also showed various emotional changes parallel to the scale of pandemic waves and corresponding public health responses. The results have potential applications such as to adjust the psychological and/or physical support extended to the nursing workforce. However, this study has several limitations that will be considered in the future study such as not validated in a healthcare professional group, small sample size, and possible bias in tweets.

Spinal Cord Injury Community Personal Opinions and Perspectives on Spinal Cord Stimulation.

Background: Spinal cord stimulation (SCS) clinical trials are evaluating its efficacy and safety for motor, sensory, and autonomic recovery following spinal cord injury (SCI). The perspectives of people living with SCI are not well known and can inform the planning, delivery, and translation of SCS. Objectives: To obtain input from people living with SCI on the top priorities for recovery, expected meaningful benefits, risk tolerance, clinical trial design, and overall interest in SCS. Methods: Data were collected anonymously from an online survey between February and May 2020. Results: A total of 223 respondents living with SCI completed the survey. The majority of respondents identified their gender as male (64%), were 10+ years post SCI (63%), and had a mean age of 50.8 years. Most individuals had a traumatic SCI (81%), and 45% classified themselves as having tetraplegia. Priorities for improved outcome for those with complete or incomplete tetraplegia included fine motor skills and upper body function, whereas priorities for complete or incomplete paraplegia included standing and walking, and bowel function. The meaningful benefits that are important to achieve are bowel and bladder care, less reliance on caregivers, and maintaining physical health. Perceived potential risks include further loss of function, neuropathic pain, and complications. Barriers to participation in clinical trials include inability to relocate, out-of-pocket expenses, and awareness of therapy. Respondents were more interested in transcutaneous SCS than epidural SCS (80% and 61%, respectively). Conclusion: SCS clinical trial design, participant recruitment, and translation of the technology can be improved by better reflecting the priorities and preferences of those living with SCI identified from this study.

Carboplatin dosing in the treatment of ovarian cancer: An NRG oncology group study.

OBJECTIVE: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl). METHODS: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event. RESULTS: AUC statistics (range, 0.52-0.64) showed log(CrClJelliffe) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%-15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively. CONCLUSION: The formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials.

Analysis of Nurse and Patient Preferences for Pre-Filled Pen Devices for Self-Injection of Highly Purified Human Menopausal Gonadotropin (HP-hMG, MENOPUR®).

Purpose: This study aimed to identify the most important attributes for a gonadotropin pen as perceived by assisted reproductive technology (ART) patients and fertility nurses, and to examine how well a prototype HP-hMG (MENOPUR®) pen reflects these preferences. Patients and Methods: This market research study incorporated a two-part survey with respondents (N=221) from Poland, Spain and the UK. Respondents included patients (n=141) who consulted a fertility specialist in the previous 2 years, and fertility nurses (n=80) who assisted in at least 75 ART cycles/year. Patients were divided into two subgroups depending on their experience with ART (experienced and naïve). Key attributes for an injection pen, as perceived by patients and nurses, were assessed via an online survey and ranked by their relative importance using Anchored Maximum Difference Scaling. After performing a dummy injection, respondents compared the attributes of an unbranded prototype pen against the key attributes identified. Results: Across all survey respondents, the ability to correct the dialed dose was considered to be the most important product attribute of a gonadotropin pen. Confidence in the patient's ability to inject correctly at home was also identified as a key attribute, considered by both nurses and naïve patients as extremely high. When considering the prototype pen device, almost all study respondents reported a positive experience (99%) with 72% rating it as "very good". The prototype pen was perceived to possess the key attributes considered important for a gonadotropin pen by patients and nurses, including correcting the dose, the ability to self-inject safely and correctly, ease of preparation and use, and an injection which appeared to be as painless as possible. Conclusion: The prototype pen was found to perform well across all key attributes, especially those considered most important in gonadotropin pens, suggesting that it is a user-friendly option for patients undergoing ART.

Lack of Awareness of Human Papillomavirus Testing Among U.S. Women.

INTRODUCTION: National surveys provide important information for public health planning. Lack of preventive screenings awareness may result in unreliable survey estimates. This study examines women's awareness of receiving human papillomavirus testing using three national surveys. METHODS: In 2022, self-reported data analyses on human papillomavirus testing status among women without hysterectomy were conducted from the 2020 Behavioral Risk Factor Surveillance System (BRFSS) (n=80,648, aged 30-64 years), the 2019 National Health Interview Survey (NHIS) (n=7,062, aged 30-65 years), and the 2017-2019 National Survey of Family Growth (n=2,973, aged 30-49 years). Associations between human papillomavirus awareness status (yes, no, don't know) and demographic characteristics were examined with generalized multinomial logistic model to generate adjusted prevalence ratios. Adjusted risk differences were assessed with the t-test for the Don't know answer. RESULTS: A total of 21.8% or >12 million in the study population of women in the BRFSS, 19.5%, (>10.5 million women) in the NHIS, and 9.4% in the National Survey of Family Growth responded don't know to human papillomavirus testing awareness status question. Women aged 40-64 years in BRFSS and 50-65 years in NHIS were more likely to answer don't know than those aged 30-34 (p<0.05 and p<0.01, respectively). Non-Hispanic White women were more likely to answer don't know than non-Hispanic Native Hawaiian/Pacific Islander, non-Hispanic Black, non-Hispanic Asian, and Hispanic women in BRFSS and non-Hispanic Black women in NHIS (adjusted prevalence ratio range=0.60-0.78; p<0.001 and adjusted prevalence ratio=0.72; p<0.001, respectively). CONCLUSIONS: One in five women was unaware of her human papillomavirus testing status, and awareness was lower among older and non-Hispanic White women. The awareness gap may affect the reliability of estimated human papillomavirus testing population uptake using survey data.

Pathogen-driven CRISPR screens identify TREX1 as a regulator of DNA self-sensing during influenza virus infection.

Intracellular pathogens interact with host factors, exploiting those that enhance replication while countering those that suppress it. Genetic screens have begun to define the host:pathogen interface and establish a mechanistic basis for host-directed therapies. Yet, limitations of current approaches leave large regions of this interface unexplored. To uncover host factors with pro-pathogen functions, we developed a novel fitness-based screen that queries factors important during the middle-to-late stages of infection. This was achieved by engineering influenza virus to direct the screen by programing dCas9 to modulate host gene expression. A genome-wide screen identified the cytoplasmic DNA exonuclease TREX1 as a potent pro-viral factor. TREX1 normally degrades cytoplasmic DNA to prevent inappropriate innate immune activation by self DNA. Our mechanistic studies revealed that this same process functions during influenza virus infection to enhance replication. Infection triggered release of mitochondrial DNA into the cytoplasm, activating antiviral signaling via cGAS and STING. TREX1 metabolized the mitochondrial DNA preventing its sensing. Collectively, these data show that self-DNA is deployed to amplify host innate sensing during RNA virus infection, a process tempered by TREX1. Moreover, they demonstrate the power and generality of pathogen driven fitness-based screens to pinpoint key host regulators of intracellular pathogens.