Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact.

Spaceflight is known to impose changes on human physiology with unknown molecular etiologies. To reveal these causes, we used a multi-omics, systems biology analytical approach using biomedical profiles from fifty-nine astronauts and data from NASA's GeneLab derived from hundreds of samples flown in space to determine transcriptomic, proteomic, metabolomic, and epigenetic responses to spaceflight. Overall pathway analyses on the multi-omics datasets showed significant enrichment for mitochondrial processes, as well as innate immunity, chronic inflammation, cell cycle, circadian rhythm, and olfactory functions. Importantly, NASA's Twin Study provided a platform to confirm several of our principal findings. Evidence of altered mitochondrial function and DNA damage was also found in the urine and blood metabolic data compiled from the astronaut cohort and NASA Twin Study data, indicating mitochondrial stress as a consistent phenotype of spaceflight.

The Evil DExH/D: Chikungunya virus runs but cannot hide from DDX39A.

In this issue, Tapescu et al.1 identify DDX39A as a novel antiviral protein that acts on conserved features of alphavirus RNA to limit infection in an IFN-independent manner.

Altered m6A Modification of Specific Cellular Transcripts Affects Flaviviridae Infection.

The RNA modification N6-methyladenosine (m6A) modulates mRNA fate and thus affects many biological processes. We analyzed m6A across the transcriptome following infection by dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), and hepatitis C virus (HCV). We found that infection by these viruses in the Flaviviridae family alters m6A modification of specific cellular transcripts, including RIOK3 and CIRBP. During viral infection, the addition of m6A to RIOK3 promotes its translation, while loss of m6A in CIRBP promotes alternative splicing. Importantly, viral activation of innate immune sensing or the endoplasmic reticulum (ER) stress response contributes to the changes in m6A in RIOK3 or CIRBP, respectively. Further, several transcripts with infection-altered m6A profiles, including RIOK3 and CIRBP, encode proteins that influence DENV, ZIKV, and HCV infection. Overall, this work reveals that cellular signaling pathways activated during viral infection lead to alterations in m6A modification of host mRNAs to regulate infection.

Challenges to mapping and defining m6A function in viral RNA.

Viral RNA molecules contain multiple layers of regulatory information. This includes features beyond the primary sequence, such as RNA structures and RNA modifications, including N6-methyladenosine (m6A). Many recent studies have identified the presence and location of m6A in viral RNA and have found diverse regulatory roles for this modification during viral infection. However, to date, viral m6A mapping strategies have limitations that prevent a complete understanding of the function of m6A on individual viral RNA molecules. While m6A sites have been profiled on bulk RNA from many viruses, the resulting m6A maps of viral RNAs described to date present a composite picture of m6A across viral RNA molecules in the infected cell. Thus, for most viruses, it is unknown if unique viral m6A profiles exist throughout infection, nor if they regulate specific viral life cycle stages. Here, we describe several challenges to defining the function of m6A in viral RNA molecules and provide a framework for future studies to help in the understanding of how m6A regulates viral infection.

The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs.

IFNL3, which encodes interferon-λ3 (IFN-λ3), has received considerable attention in the hepatitis C virus (HCV) field, as many independent genome-wide association studies have identified a strong association between polymorphisms near IFNL3 and clearance of HCV. However, the mechanism underlying this association has remained elusive. In this study, we report the identification of a functional polymorphism (rs4803217) in the 3' untranslated region (UTR) of IFNL3 mRNA that dictated transcript stability. We found that this polymorphism influenced AU-rich element (ARE)-mediated decay (AMD) of IFNL3 mRNA, as well as the binding of HCV-induced microRNAs during infection. Together these pathways mediated robust repression of the unfavorable IFNL3 polymorphism. Our data reveal a previously unknown mechanism by which HCV attenuates the antiviral response and indicate new potential therapeutic targets for HCV treatment.

Structure-first identification of RNA elements that regulate dengue virus genome architecture and replication.

The genomes of RNA viruses encode the information required for replication in host cells both in their linear sequence and in complex higher-order structures. A subset of these RNA genome structures show clear sequence conservation, and have been extensively described for well-characterized viruses. However, the extent to which viral RNA genomes contain functional structural elements-unable to be detected by sequence alone-that nonetheless are critical to viral fitness is largely unknown. Here, we devise a structure-first experimental strategy and use it to identify 22 structure-similar motifs across the coding sequences of the RNA genomes for the four dengue virus serotypes. At least 10 of these motifs modulate viral fitness, revealing a significant unnoticed extent of RNA structure-mediated regulation within viral coding sequences. These viral RNA structures promote a compact global genome architecture, interact with proteins, and regulate the viral replication cycle. These motifs are also thus constrained at the levels of both RNA structure and protein sequence and are potential resistance-refractory targets for antivirals and live-attenuated vaccines. Structure-first identification of conserved RNA structure enables efficient discovery of pervasive RNA-mediated regulation in viral genomes and, likely, other cellular RNAs.

N6-Methyladenosine Regulates Host Responses to Viral Infection.

Recent discoveries have revealed that, during viral infection, the presence of the RNA modification N6-methyladenosine (m6A) on viral and cellular RNAs has profound impacts on infection outcome. Although m6A directly regulates many viral RNA processes, its effects on cellular RNAs and pathways during infection have only recently begun to be elucidated. Disentangling the effects of m6A on viral and host RNAs remains a challenge for the field. m6A has been found to regulate host responses such as viral RNA sensing, cytokine responses, and immune cell functions. We highlight recent findings describing how m6A modulates host responses to viral infection and discuss future directions that will lead to a synergistic understanding of the processes by which m6A regulates viral infection.

Virology-the path forward.

In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology research is paramount and oversight frameworks should be reviewed periodically. Changes should be made with care, however, to avoid impeding science that is essential for rapidly reducing and responding to pandemic threats as well as addressing more common challenges caused by infectious diseases. Decades of research uniquely positioned the US to be able to respond to the COVID-19 crisis with astounding speed, delivering life-saving vaccines within a year of identifying the virus. We should embolden and empower this strength, which is a vital part of protecting the health, economy, and security of US citizens. Herein, we offer our perspectives on priorities for revised rules governing virology research in the US.

An Atom-Precise Understanding of DNA-Stabilized Silver Nanoclusters.

ConspectusDNA-stabilized silver nanoclusters (AgN-DNAs) are sequence-encoded fluorophores. Like other noble metal nanoclusters, the optical properties of AgN-DNAs are dictated by their atomically precise sizes and shapes. What makes AgN-DNAs unique is that nanocluster size and shape are controlled by nucleobase sequence of the templating DNA oligomer. By choice of DNA sequence, it is possible to synthesize a wide range of AgN-DNAs with diverse emission colors and other intriguing photophysical properties. AgN-DNAs hold significant potential as "programmable" emitters for biological imaging due to their combination of small molecular-like sizes, bright and sequence-tuned fluorescence, low toxicities, and cost-effective synthesis. In particular, the potential to extend AgN-DNAs into the second near-infrared region (NIR-II) is promising for deep tissue imaging, which is a major area of interest for advancing biomedical imaging. Achieving this goal requires a deep understanding of the structure-property relationships that govern AgN-DNAs in order to design AgN-DNA emitters with sizes and geometries that support NIR-II emission.In recent years, major advances have been made in understanding the structure and composition of AgN-DNAs, enabling new insights into the correlation of nanocluster structure and photophysical properties. These advances have hinged on combined innovations in mass characterization and crystallography of compositionally pure AgN-DNAs, together with combinatorial experiments and machine learning-guided design. A combined approach is essential due to the major challenge of growing suitable AgN-DNA crystals for diffraction and to the labor-intensive nature of preparing and solving the molecular formulas of atomically precise AgN-DNAs by mass spectrometry. These approaches alone are not feasibly scaled to explore the large sequence space of DNA oligomer templates for AgN-DNAs.This account describes recent fundamental advances in AgN-DNA science that have been enabled by high throughput synthesis and fluorimetry together with detailed analytical studies of purified AgN-DNAs. First, short introductions to nanocluster chemistry and AgN-DNA basics are presented. Then, we review recent large-scale studies that have screened thousands of DNA templates for AgN-DNAs, leading to discovery of distinct classes of these emitters with unique cluster core compositions and ligand chemistries. In particular, the discovery of a new class of chloride-stabilized AgN-DNAs enabled the first ab initio calculations of AgN-DNA electronic structure and present new approaches to stabilize these emitters in biologically relevant conditions. Near-infrared (NIR) emissive AgN-DNAs are also found to exhibit diverse structures and properties. Finally, we conclude by highlighting recent proof-of-principle demonstrations of NIR AgN-DNAs for targeted fluorescence imaging. Continued efforts may future push AgN-DNAs into the tissue transparency window for fluorescence imaging in the NIR-II tissue transparency window.

Signaling from the RNA sensor RIG-I is regulated by ufmylation.

The RNA-binding protein RIG-I is a key initiator of the antiviral innate immune response. The signaling that mediates the antiviral response downstream of RIG-I is transduced through the adaptor protein MAVS and results in the induction of type I and III interferons (IFNs). This signal transduction occurs at endoplasmic reticulum (ER)­mitochondrial contact sites, to which RIG-I and other signaling proteins are recruited following their activation. RIG-I signaling is highly regulated to prevent aberrant activation of this pathway and dysregulated induction of IFN. Previously, we identified UFL1, the E3 ligase of the ubiquitin-like modifier conjugation system called ufmylation, as one of the proteins recruited to membranes at ER­mitochondrial contact sites in response to RIG-I activation. Here, we show that UFL1, as well as the process of ufmylation, promote IFN induction in response to RIG-I activation. We found that following RNA virus infection, UFL1 is recruited to the membrane-targeting protein 14­3-3ε and that this complex is then recruited to activated RIG-I to promote downstream innate immune signaling. Importantly, we found that 14­3-3ε has an increase in UFM1 conjugation following RIG-I activation. Additionally, loss of cellular ufmylation prevents the interaction of 14­3-3ε with RIG-I, which abrogates the interaction of RIG-I with MAVS and thus the downstream signal transduction that induces IFN. Our results define ufmylation as an integral regulatory component of the RIG-I signaling pathway and as a posttranslational control for IFN induction.

How RNA modifications regulate the antiviral response.

Induction of the antiviral innate immune response is highly regulated at the RNA level, particularly by RNA modifications. Recent discoveries have revealed how RNA modifications play key roles in cellular surveillance of nucleic acids and in controlling gene expression in response to viral infection. These modifications have emerged as being essential for a functional antiviral response and maintaining cellular homeostasis. In this review, we will highlight these and other discoveries that describe how the antiviral response is controlled by modifications to both viral and cellular RNA, focusing on how mRNA cap modifications, N6-methyladenosine, and RNA editing all contribute to coordinating an efficient response that properly controls viral infection.

The effect of GLP-1 receptor agonist use on negative evaluations of women with higher and lower body weight.

BACKGROUND: GLP-1 receptor agonists (GLP-1 RAs) have dramatically altered obesity treatment. Media reports suggest that GLP-1 RAs users often report feeling judged for taking a "shortcut" to lose weight, which may be related to negative stereotypes toward people with larger bodies. Media reports also describe negative attitudes about lean people who take GLP-1 RAs to enhance their appearance. The present research used a 2 × 2 experimental design to test the effects of GLP-1 RA use and body size on attitudes and egocentric impressions. SUBJECTS/METHODS: A sample of 357 U.S. adults (Mage = 37.8, SD = 13) were randomly assigned to read about a woman, who either was lean or had obesity, and who lost 15% of her body weight either with diet/exercise or a GLP-1 RA. Participants answered questions measuring endorsement of negative weight-related stereotypes and egocentric attitudes toward the woman, as well as beliefs that she took a shortcut to lose weight and beliefs that biogenetic factors caused her baseline weight. RESULTS: Negative evaluations and egocentric impressions were stronger toward a woman who lost weight with a GLP-1 RA compared to diet/exercise. Losing weight with a GLP-1 RA led to stronger negative evaluations through higher weight loss shortcut beliefs irrespective of body size. Losing weight with a GLP-1 RA also led to higher egocentric impressions through higher shortcut beliefs, and this effect was stronger for a lean woman. Finally, losing weight with a GLP-1 RA led to more negative evaluations through stronger endorsement of biogenetic causal beliefs for a lean woman only. CONCLUSIONS: This timely study provides evidence that people with larger and smaller bodies alike are at-risk for being judged for using GLP-1 RAs due to beliefs that these medications are a shortcut. Findings also demonstrate novel reactions related to egotism when weight loss is achieved with pharmacological interventions. PRE-REGISTRATION AND DATA: osf.io/xme4w.

RNA modification of an RNA modifier prevents self-RNA sensing.

A new study in PLOS Biology finds that interferon (IFN)-induced adenosine deaminase acting on RNA 1 (ADAR1) mRNA is N6-methyladenosine (m6A) modified to promote its translation, enabling ADAR1 to modify self-double-stranded RNAs (dsRNAs) generated during the IFN response and preventing activation of the melanoma differentiation-associated protein 5 (MDA5)-mediated host antiviral response.

Combined Robotic Ventral Mesh Rectopexy and Sacrocolpopexy for Multicompartmental Pelvic Organ Prolapse.

BACKGROUND: Multispecialty management should be the preferred approach for the treatment of pelvic floor dysfunction because there is often multicompartmental prolapse. OBJECTIVE: To assess the safety of combined robotic ventral mesh rectopexy and either uterine or vaginal fixation for the treatment of multicompartmental pelvic organ prolapse at our institution. DESIGN: Retrospective analysis. SETTINGS: Tertiary referral academic center. PATIENTS: All patients who underwent a robotic approach and combined procedure and whose cases were discussed at a biweekly pelvic floor multidisciplinary team meeting. MAIN OUTCOME MEASURES: Operative time, intraoperative blood loss and complications, postoperative pelvic organ prolapse quantification score, length of stay, 30-day morbidity, and readmission. RESULTS: From 2018 to 2021, there were 321 operations for patients with multicompartmental prolapse. The mean age was 63.4 years. The predominant pelvic floor dysfunction was rectal prolapse in 170 cases (60%). Pelvic organ prolapse quantification scores were II in 146 patients (53%), III in 121 patients (44%), and IV in 9 patients (3%); 315 of 323 cases included robotic ventral mesh rectopexy (98%). Sacrocolpopexy or sacrohysteropexy was performed in 281 patients (89%). Other procedures included 175 hysterectomies (54%), 104 oophorectomies (32%), 151 sling procedures (47%), 149 posterior repairs (46%), and 138 cystocele repairs (43%). The operative time for ventral mesh rectopexy was 211 minutes and for combined pelvic floor reconstruction was 266 minutes. Average length of stay was 1.6 days. Eight patients were readmitted within 30 days: 1 with a severe headache and 7 with postoperative complications (2.5%), such as pelvic collection and perirectal collection, both requiring radiologic drainage. Four complications required reoperation: epidural abscess, small-bowel obstruction, missed enterotomy requiring resection, and urinary retention requiring sling revision. There were no mortalities. LIMITATIONS: Retrospective single-center study. CONCLUSIONS: A combined robotic approach for multicompartmental pelvic organ prolapse is a safe and viable procedure with a relatively low rate of morbidity and no mortality. This is the highest volume series of combined robotic pelvic floor reconstruction in the literature and demonstrates a low complication rate and short length of stay. See Video Abstract . RECTOPEXIA Y SACROCOLPOPEXIA ROBTICA VENTRAL COMBINADAS CON MALLA PARA EL PROLAPSO DE RGANOS PLVICOS MULTICOMPARTIMENTALES: ANTECEDENTES:El tratamiento multiespecializado debe ser el enfoque preferido para el tratamiento de la disfunción del suelo pélvico, ya que a menudo hay prolapso multicompartimental.OBJETIVO:Evaluar la seguridad de la rectopexia robótica combinada con malla ventral y fijación uterina o vaginal para el tratamiento del prolapso multicompartimental de órganos pélvicos en nuestra institución.DISEÑO:Análisis retrospectivo.AJUSTES:Centro académico de referencia terciarioPACIENTES:Todos los pacientes que se sometieron a un enfoque robótico y un procedimiento combinado y se discutieron en una reunión quincenal del equipo multidisciplinario sobre el piso pélvico.MEDIDAS DE RESULTADO:Tiempo operatorio, pérdida de sangre intraoperatoria y complicaciones. Puntuación de cuantificación del prolapso de órganos pélvicos posoperatorio, duración de la estancia hospitalaria, morbilidad a 30 días y reingreso.RESULTADOS:De 2018 a 2021, se realizaron 321 operaciones de pacientes con prolapso multicompartimental. La edad media fue 63.4 años. La disfunción del suelo pélvico predominante fue el prolapso rectal en 170 casos (60%). Las puntuaciones de cuantificación del prolapso de órganos pélvicos fueron II en 146 pacientes (53%), III en 121 (44%) y IV en 9 (3%); 315 de los 323 casos incluyeron rectopexia robótica de malla ventral (98%). Se realizó sacrocolpopexia o sacrohisteropexia en 281 pacientes (89%). Otros procedimientos incluyeron 175 histerectomías (54%), 104 ooforectomías (32%), 151 procedimientos de cabestrillo (47%), 149 reparaciones posteriores (46%) y 138 reparaciones de cistocele (43%). El tiempo operatorio para la rectopexia con malla ventral fue de 211 minutos y la reconstrucción combinada del piso pélvico de 266 minutos. La estancia media fue de 1.6 días. Ocho pacientes reingresaron dentro de los 30 días, 1 con dolor de cabeza intenso y 7 pacientes con complicaciones posoperatorias (2.5%): colección pélvica y colección perirrectal, ambas requirieron drenaje radiológico. Cuatro complicaciones requirieron reoperación: absceso epidural, obstrucción del intestino delgado, enterotomía omitida que requirió resección y retención urinaria que requirió revisión del cabestrillo. No hubo mortalidades.LIMITACIONES:Estudio retrospectivo unicéntrico.CONCLUSIONES:Un enfoque robótico combinado para el prolapso multicompartimental de órganos pélvicos es un procedimiento seguro y viable con una tasa relativamente baja de morbilidad y ninguna mortalidad. Esta es la serie de mayor volumen de reconstrucción robótica combinada del suelo pélvico en la literatura y demuestra una baja tasa de complicaciones y una estancia hospitalaria corta. (Traducción-Dr. Aurian Garcia Gonzalez )See Editorial on page 195.

Educational Strategies in Pediatric Trauma Resuscitation Across Disciplines: A Scoping Review.

INTRODUCTION: Trauma is the leading cause of death and disability in children. Differences in mechanism, injury pattern, severity, and physiology in this population distinguish pediatric trauma patients from adults. Educational techniques including simulation and didactics may improve pediatric readiness in this setting. We summarize the literature across disciplines, highlighting the curricular approaches, target provider population, educational content, content delivery method, and Kirkpatrick level for pediatric trauma resuscitation education. METHODS: The MEDLINE (via Ovid), Embase (via Elsevier), Cumulative Index to Nursing & Allied Health Literature Complete (via EBSCO), Education Database (via ProQuest), and Web of Science Social Science Citation Index and Science Citation Index (via Clarivate) were searched. We reviewed 90 manuscripts describing pediatric trauma resuscitation education programs. When available, target provider population, curricular content, delivery method, and Kirkpatrick level were obtained. RESULTS: Nurses (50%), residents (45%), and attending physicians (43%) were the most common participants. Airway management (25%), shock (25%), and general trauma (25%) were the most frequently taught concepts, and delivery of content was more frequently via simulation (65%) or didactics (52%). Most studies (39%) were Kirkpatrick Level 1. CONCLUSIONS: This review suggests that diverse strategies exist to promote pediatric readiness. Most training programs are interdisciplinary and use a variety of educational techniques. However, studies infrequently report examining the impact of educational interventions on patient-centered outcomes and lack detail in describing their curriculum. Future educational efforts would benefit from heightened attention to such outcome measures and a rigorous description of their curricula to allow for reproducibility.

A Peer-to-Peer Collaborative Learning Approach for the Implementation of Evidence-Informed Interventions to Improve HIV-Related Health Outcomes.

The nationwide scale-up of evidence-based and evidence-informed interventions has been widely recognized as a crucial step in ending the HIV epidemic. Although the successful delivery of interventions may involve intensive expert training, technical assistance (TA), and dedicated funding, most organizations attempt to replicate interventions without access to focused expert guidance. Thus, there is a grave need for initiatives that meaningfully address HIV health disparities while addressing these inherent limitations. Here, the Health Resources and Services Administration HIV/AIDS Bureau (HRSA HAB) initiative Using Evidence-Informed Interventions to Improve HIV Health Outcomes among People Living with HIV (E2i) piloted an alternative approach to implementation that de-emphasized expert training to naturalistically simulate the experience of future HIV service organizations with limited access to TA. The E2i approach combined the HAB-adapted Institute for Healthcare Improvement's Breakthrough Series Collaborative Learning Model with HRSA HAB's Implementation Science Framework, to create an innovative multi-tiered system of peer-to-peer learning that was piloted across 11 evidence-informed interventions at 25 Ryan White HIV/AIDS Program sites. Four key types of peer-to-peer learning exchanges (i.e., intervention, site, staff role, and organization specific) took place at biannual peer learning sessions, while quarterly intervention cohort calls and E2i monthly calls with site staff occurred during the action periods between learning sessions. Peer-to-peer learning fostered both experiential learning and community building and allowed site staff to formulate robust site-specific action plans for rapid cycle testing between learning sessions. Strategies that increase the effectiveness of interventions while decreasing TA could provide a blueprint for the rapid uptake and integration of HIV interventions nationwide.

How should artificial intelligence be used in Australian health care? Recommendations from a citizens' jury.

OBJECTIVE: To support a diverse sample of Australians to make recommendations about the use of artificial intelligence (AI) technology in health care. STUDY DESIGN: Citizens' jury, deliberating the question: "Under which circumstances, if any, should artificial intelligence be used in Australian health systems to detect or diagnose disease?" SETTING, PARTICIPANTS: Thirty Australian adults recruited by Sortition Foundation using random invitation and stratified selection to reflect population proportions by gender, age, ancestry, highest level of education, and residential location (state/territory; urban, regional, rural). The jury process took 18 days (16 March - 2 April 2023): fifteen days online and three days face-to-face in Sydney, where the jurors, both in small groups and together, were informed about and discussed the question, and developed recommendations with reasons. Jurors received extensive information: a printed handbook, online documents, and recorded presentations by four expert speakers. Jurors asked questions and received answers from the experts during the online period of the process, and during the first day of the face-to-face meeting. MAIN OUTCOME MEASURES: Jury recommendations, with reasons. RESULTS: The jurors recommended an overarching, independently governed charter and framework for health care AI. The other nine recommendation categories concerned balancing benefits and harms; fairness and bias; patients' rights and choices; clinical governance and training; technical governance and standards; data governance and use; open source software; AI evaluation and assessment; and education and communication. CONCLUSIONS: The deliberative process supported a nationally representative sample of citizens to construct recommendations about how AI in health care should be developed, used, and governed. Recommendations derived using such methods could guide clinicians, policy makers, AI researchers and developers, and health service users to develop approaches that ensure trustworthy and responsible use of this technology.

Acute cancer-related symptoms and concerns among patients receiving chemotherapy: current state of the science.

PURPOSE: This study provides an updated evaluation of the prevalence and severity of acute cancer-related symptoms and quality of life (QOL) concerns among patients treated with emetogenic chemotherapy. METHODS: Patients were recruited to a larger, multi-site observational study prior to starting chemotherapy. Participants completed sociodemographic questionnaires and clinical data were abstracted via medical record review. Symptoms and QOL were assessed 5 days after starting moderately or highly emetogenic chemotherapy. Functional Assessment of Cancer Therapy - General assessed QOL concerns. Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events evaluated symptoms. Symptoms were considered severe when participants responded "severe" or "very severe." RESULTS: Participants (N = 1174) were on average 58 ± 13 years, mostly female (73%), non-Hispanic (89%), and White (87%). Most participants were diagnosed with breast (38.1%), gynecological (20%), and gastrointestinal (17.1%) cancer. The most common QOL concerns of any severity were fatigue (94%), anhedonia (89%), dissatisfaction with QOL (86%), and sleep disturbance (86%). The most common severe QOL concerns were anhedonia (44%), fatigue (40%), and inability to work (38%). Decreased appetite (74%), pain (71%), and constipation (70%) were the most common symptoms of any severity, as well as most common severe symptoms (13%, 18%, and 18%, respectively). CONCLUSION: Herein, updates are provided in regard to QOL concerns and symptoms reported by patients in the days after chemotherapy and demonstrates that concerns and symptoms have shifted in the last decade.

Robotic Vaginal Hernia Repair for Recurrent Vaginal Prolapse Status Post-Radical Cystectomy with an Indiana Pouch.

INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse following a radical cystectomy is challenging to treat and recurrence of prolapse after primary repair is common owing to compromised pelvic floor support and tissue quality. Vaginal prolapse repairs are often preferred because of concern for patients' complex intraabdominal pathological conditions. However, for those with recurrent prolapse following colpocleisis, limited definitive treatment options exist. METHODS: This surgical video presents a 64-year-old G4P4 with a history of radical cystectomy with an Indiana Pouch for invasive urothelial carcinoma who presented with recurrent stage IV vaginal prolapse two years following colpocleisis. Owing to thin vaginal tissue, a sacrocolpopexy with vaginal mesh could not be performed, thus, the patient underwent robotic-assisted vaginal hernia repair with a polypropylene-reinforced ovine tissue matrix attached to Cooper's ligament and the levator ani muscles. RESULTS: The surgery was free from complications and her postoperative Pelvic Organ Prolapse Quantification examination revealed a leading vaginal tissue remnant at the level of the hymen. The patient reported overall improved health and quality of life following surgery and recovery on postoperative validated questionnaires. CONCLUSIONS: Vaginal and pelvic floor hernia repair with a polypropylene-reinforced tissue matrix is a feasible definitive surgical treatment for patients with prior radical cystectomy in whom colpocleisis has failed.

Public values to guide childhood vaccination mandates: A report on four Australian community juries.

OBJECTIVE: Governments use vaccination mandates, of different degrees of coerciveness, to encourage or require childhood vaccination. We elicited the views of well-informed community members on the public acceptability of using childhood vaccination mandates in Australia. METHODS: Four community juries were conducted in Canberra, Launceston, Cairns and Melbourne, Australia between 2021 and 2022. We recruited 51 participants from diverse backgrounds, genders and ages through random digit dialling and social media. Two juries were held in metropolitan areas, and two in regional/rural settings. Outcome measures included jury verdicts and reasons in response to structured questions. RESULTS: All juries were concerned about collective protection and individual rights but prioritised the former over the latter. A majority in all juries supported mandates but juries disagreed with respect to the appropriate mandate types. All juries endorsed using the least restrictive or coercive means to encourage vaccination (providing incentives or education, e.g.) before imposing penalties such as financial losses and school exclusions. The overriding view was that it is fairer to place a direct burden on parents rather than children and that mandates should be designed to avoid inequitable impacts on less advantaged groups in society. Many jurors found conscientious objection acceptable as a controlled option for resolute refusers, provided that overall vaccination coverage remains high. CONCLUSION: This paper gives policymakers access to the reasons that Australians have for supporting or opposing different mandates under conditions of high knowledge, understanding and deliberation regarding policy options. Sustaining high rates of vaccination requires high levels of co-operation between governments, public health actors and the public. Our findings highlight the importance of considering public values in the design and implementation of vaccination mandates. PATIENT AND PUBLIC INVOLVEMENT: We sought input from individuals who did and did not vaccinate during the study design. The views and perspectives of nonvaccinating parents were presented in the evidence to juries. We deliberately excluded nonvaccinating individuals from participating, as the divisive and often hostile nature of the topic, and their minority status, made it difficult to ensure they would feel safe as members of the jury without overrepresenting their perspective in the sample. Two related projects engaged directly with these parents.