Trophoblast Side-Population Markers are Dysregulated in Preeclampsia and Fetal Growth Restriction.

Dysregulated progenitor cell populations may contribute to poor placental development and placental insufficiency pathogenesis. Side-population cells possess progenitor properties. Recent human trophoblast side-population isolation identified enrichment of 8 specific genes (CXCL8, ELL2, GATA6, HK2, HLA-DPB1, INTS6, SERPINE3 and UPP1) (Gamage et al. 2020, Stem Cell Rev Rep). We characterised these trophoblast side-population markers in human placenta and in placental insufficiency disorders: preeclampsia and fetal growth restriction (FGR). Trophoblast side-population markers localised to mononuclear trophoblasts lining the placental villous basement membrane in preterm control, preeclamptic and FGR placental sections (n = 3, panel of 3 markers/serial section). Analysis of single-cell transcriptomics of an organoid human trophoblast stem cell (hTSC) to extravillous trophoblast (EVT) differentiation model (Shannon et al. 2022, Development) identified that all side-population genes were enriched in mononuclear trophoblast and trophoblasts committed to differentiation under hTSC culture conditions. In vitro validation via 96 h time course hTSC differentiation to EVTs or syncytiotrophoblasts (n = 5) demonstrated ELL2 and HK2 increased with differentiation (p < 0.0024, p < 0.0039 respectively). CXCL8 and HLA-DPB1 were downregulated (p < 0.030, p < 0.011 respectively). GATA6 and INTS6 increased with EVT differentiation only, and UPP1 reduced with syncytialisation. SERPINE3 was undetectable. Trophoblast side-population marker mRNA was measured in human placentas (< 34-weeks' gestation; n = 78 preeclampsia, n = 30 FGR, and n = 18 gestation-matched controls). ELL2, HK2 and CXCL8 were elevated in preeclamptic (p = 0.0006, p < 0.0001, p = 0.0335 respectively) and FGR placentas (p = 0.0065, p < 0.0001, p = 0.0001 respectively) versus controls. Placental GATA6 was reduced in pregnancies with preeclampsia and FGR (p = 0.0014, p = 0.0146 respectively). Placental INTS6 was reduced with FGR only (p < 0.0001). This study identified the localisation of a unique trophoblast subset enriched for side-population markers. Aberrant expression of some side-population markers may indicate disruptions to unique trophoblast subtypes in placental insufficiency.

The Year in Perioperative Echocardiography: Selected Highlights from 2023.

This article is the eighth in an annual series reviewing the research highlights of the year pertaining to the subspecialty of perioperative echocardiography for the Journal of Cardiothoracic and Vascular Anesthesia. The authors thank the editor-in-chief, Dr Kaplan, and the editorial board for the opportunity to continue this series. In most cases, these will be research articles targeted at the perioperative echocardiographic diagnosis and treatment of patients after cardiothoracic surgery; but in some cases, the articles will target the use of perioperative echocardiography in general.

Ehf controls mammary alveolar lineage differentiation and is a putative suppressor of breast tumorigenesis.

The transcription factor EHF is highly expressed in the lactating mammary gland, but its role in mammary development and tumorigenesis is not fully understood. Utilizing a mouse model of Ehf deletion, herein, we demonstrate that loss of Ehf impairs mammary lobuloalveolar differentiation at late pregnancy, indicated by significantly reduced levels of milk genes and milk lipids, fewer differentiated alveolar cells, and an accumulation of alveolar progenitor cells. Further, deletion of Ehf increased proliferative capacity and attenuated prolactin-induced alveolar differentiation in mammary organoids. Ehf deletion also increased tumor incidence in the MMTV-PyMT mammary tumor model and increased the proliferative capacity of mammary tumor organoids, while low EHF expression was associated with higher tumor grade and poorer outcome in luminal A and basal human breast cancers. Collectively, these findings establish EHF as a non-redundant regulator of mammary alveolar differentiation and a putative suppressor of mammary tumorigenesis.

Social Anxiety Symptoms in Adolescents and Young Adults Recently Diagnosed with Cancer.

Purpose: Social anxiety disorder (SAD) remains an understudied potential link between the cancer experience and adolescent and young adult (AYA) cancer survivors' poor psychosocial outcomes. We investigated the frequency and duration of, as well as factors associated with, symptoms of SAD among AYAs with cancer. Methods: This longitudinal, mixed-methods study involved online surveys (including a validated screening tool for SAD) at recruitment and 6 months later, and a structured clinical interview. Results: Twenty-eight AYAs (aged 12-30 years, <1-year postdiagnosis, 50% male) completed the first survey (M = 6 months postdiagnosis). About 32% reported clinically significant SAD symptoms. Fourteen completed the follow-up survey (M = 12 months postdiagnosis), of which 9 (62%) reported persistent or worse symptoms of SAD significantly associated with emotional distress, physical appearance concerns, negative social cognitions, and depression. Conclusion: A subset of AYAs with cancer may experience clinically significant SAD symptoms that can affect their psychosocial well-being. Further work on how to best identify and support AYAs with SAD is needed.

Exploring Web-Based Information and Resources That Support Adolescents and Young Adults With Cancer to Resume Study and Work: Environmental Scan Study.

BACKGROUND: Adolescents and young adults (AYAs) diagnosed with cancer experience physical, cognitive, and psychosocial effects from cancer treatment that can negatively affect their ability to remain engaged in education or work through cancer treatment and in the long term. Disengagement from education or work can have lasting implications for AYAs' financial independence, psychosocial well-being, and quality of life. Australian AYAs with cancer lack access to adequate specialist support for their education and work needs and report a preference for web-based support that they can access from anywhere, in their own time. However, it remains unclear what web-based resources exist that are tailored to support AYAs with cancer in reaching their educational or work goals. OBJECTIVE: This study aimed to determine what web-based resources exist for Australian AYAs with cancer to (1) support return to education or work and (2) identify the degree to which existing resources are age-specific, cancer-specific, culturally inclusive, and evidence-based; are co-designed with AYAs; use age-appropriate language; and are easy to find. METHODS: We conducted an environmental scan by searching Google with English search terms in August 2022 to identify information resources about employment and education for AYAs ever diagnosed with cancer. Data extraction was conducted in Microsoft Excel, and the following were assessed: understandability and actionability (using the Patient Education and Materials Tool), readability (using the Sydney Health Literacy Laboratory Health Literacy Editor), and whether the resource was easy to locate, evidence-based, co-designed with AYAs, and culturally inclusive of Aboriginal and Torres Strait Islander peoples. The latter was assessed using 7 criteria previously developed by members of the research team. RESULTS: We identified 24 web-based resources, comprising 22 written text resources and 12 video resources. Most resources (21/24, 88%) were published by nongovernmental organizations in Australia, Canada, the United States, and the United Kingdom. A total of 7 resources focused on education, 8 focused on work, and 9 focused on both education and work. The evaluation of resources demonstrated poor understandability and actionability. Resources were rarely evidence-based or co-designed by AYAs, difficult to locate on the internet, and largely not inclusive of Aboriginal and Torres Strait Islander populations. CONCLUSIONS: Although web-based resources for AYAs with cancer are often available through the websites of hospitals or nongovernmental organizations, this environmental scan suggests they would benefit from more evidence-based and actionable resources that are available in multiple formats (eg, text and audio-visual) and tailored to be age-appropriate and culturally inclusive.

BECLIN1 is essential for intestinal homeostasis involving autophagy-independent mechanisms through its function in endocytic trafficking.

Autophagy-related genes have been closely associated with intestinal homeostasis. BECLIN1 is a component of Class III phosphatidylinositol 3-kinase complexes that orchestrate autophagy initiation and endocytic trafficking. Here we show intestinal epithelium-specific BECLIN1 deletion in adult mice leads to rapid fatal enteritis with compromised gut barrier integrity, highlighting its intrinsic critical role in gut maintenance. BECLIN1-deficient intestinal epithelial cells exhibit extensive apoptosis, impaired autophagy, and stressed endoplasmic reticulum and mitochondria. Remaining absorptive enterocytes and secretory cells display morphological abnormalities. Deletion of the autophagy regulator, ATG7, fails to elicit similar effects, suggesting additional novel autophagy-independent functions of BECLIN1 distinct from ATG7. Indeed, organoids derived from BECLIN1 KO mice show E-CADHERIN mislocalisation associated with abnormalities in the endocytic trafficking pathway. This provides a mechanism linking endocytic trafficking mediated by BECLIN1 and loss of intestinal barrier integrity. Our findings establish an indispensable role of BECLIN1 in maintaining mammalian intestinal homeostasis and uncover its involvement in endocytic trafficking in this process. Hence, this study has important implications for our understanding of intestinal pathophysiology.

PRMT1 acts as a suppressor of MHC-I and anti-tumor immunity.

Cancer immunotherapies have demonstrated remarkable success; however, the majority of patients do not respond or develop resistance. Here, we conduct epigenetic gene-targeted CRISPR-Cas9 screens to identify epigenomic factors that limit CD8+ T cell-mediated anti-tumor immunity. We identify that PRMT1 suppresses interferon gamma (Ifnγ)-induced MHC-I expression, thus dampening CD8+ T cell-mediated killing. Indeed, PRMT1 knockout or pharmacological targeting of type I PRMT with the clinical inhibitor GSK3368715 enhances Ifnγ-induced MHC-I expression through elevated STAT1 expression and activation, while re-introduction of PRMT1 in PRMT1-deficient cells reverses this effect. Importantly, loss of PRMT1 enhances the efficacy of anti-PD-1 immunotherapy, and The Cancer Genome Atlas analysis reveals that PRMT1 expression in human melanoma is inversely correlated with expression of human leukocyte antigen molecules, infiltration of CD8+ T cells, and overall survival. Taken together, we identify PRMT1 as a negative regulator of anti-tumor immunity, unveiling clinical type I PRMT inhibitors as immunotherapeutic agents or as adjuncts to existing immunotherapies.

The post-operative tonsillectomy (POPT) study: A multi-centre prospective paediatric cohort study.

OBJECTIVES: Tonsillectomy is the most common operation performed by otolaryngologists in the UK, despite this we have a poor understanding of the post-operative recovery. We aimed to investigate post-operative bleeding and pain following paediatric tonsillectomy using a patient diary. DESIGN: Prospective observational cohort study. SETTING: Multi-centre study involving 12 secondary and tertiary otolaryngology units across the North of England. Patients were recruited from 1st March 2020 to 30th June 2022. Multilevel ordered logistic regression model statistics were performed. PARTICIPANTS: Children (≥4 years, ≤16 years) undergoing tonsillectomy (with or without adenoidectomy) for benign pathology. MAIN OUTCOME MEASURES: Frequency and severity of post-operative bleeding. Intensity and pattern of post-operative pain. RESULTS: In total 297 children were recruited, with 91 (30.6%) diaries eligible for analysis. Post-operative bleeding occurred in 44% of children. Most frequently blood in the saliva was reported (82.9%). Increasing age significantly increased bleeding odds by 17% per year (p = .001). Bleeding frequency decreased with higher surgeon grade (p = .003) and when performing intracapsular coblation tonsillectomy (p = .02) compared with other techniques. Lower age and intracapsular coblation tonsillectomy, against other techniques, significantly reduced rates of pain post-operatively (p < .0001 and p = .0008). CONCLUSION: A high level of low-level post-operative bleeding was observed. Pain scores remained high for 5 days post-operatively then gradually reduce to normal by day 13. Intracapsular coblation tonsillectomy appears to be superior to all other techniques in terms of reducing post-operative bleeding and pain. These findings should be used to guide patients in the consent process to inform them of the expected nature of post-surgical recovery.

Guidelines for Caring for the Social Well-Being of Adolescents and Young Adults with Cancer in Australia.

More than 1000 Australian adolescents and young adults (AYAs) are diagnosed with cancer annually. Many report unmet social well-being needs, which impact their mental health. Australian AYA cancer care providers lack guidance to address these needs well. We aimed to develop guidelines for caring for the social well-being of AYAs with cancer in Australia. Following the Australian National Health and Medical Research Council guidance, we formed a multidisciplinary working group (n = 4 psychosocial researchers, n = 4 psychologists, n = 4 AYA cancer survivors, n = 2 oncologists, n = 2 nurses, and n = 2 social workers), defined the scope of the guidelines, gathered evidence via a systematic review, graded the evidence, and surveyed AYA cancer care providers about the feasibility and acceptability of the guidelines. The guidelines recommend which AYAs should have their social well-being assessed, who should lead that assessment, when assessment should occur with which tools/measures, and how clinicians can address AYAs' social well-being concerns. A key clinician, who is knowledgeable about AYAs' developmental needs, should lead the assessment of social well-being during and after cancer treatment. The AYA Psycho-Oncology Screening Tool is recommended to screen for social well-being needs. The HEADSSS Assessment (Home, Education/Employment, Eating/Exercise, Activities/Peer Relationships, Drug use, Sexuality, Suicidality/Depression, Safety/Spirituality Assessment) can be used for in-depth assessment of social well-being, while the Social Phobia Inventory can be used to assess social anxiety. AYA cancer care providers rated the guidelines as highly acceptable, but discussed many feasibility barriers. These guidelines provide an optimal care pathway for the social well-being of AYAs with cancer. Future research addressing implementation is critical to meet AYAs' social well-being needs.

Highlights and Perioperative Implications from the 2022 American College of Cardiology and American Heart Association Guidelines for Diagnosis and Management of Aortic Disease.

As the understanding of aortic diseases and their complications grow, increasing importance of uniformity in diagnosis and management is crucial for optimal care of this patient population. The 2022 American College of Cardiology and American Heart Association Guidelines for Diagnosis and Management of Aortic Disease discusses these considerations in detail. The purpose of this review is to highlight essential recommendations that are of relevance to the perioperative physician who manages these patients. A few notable points include, shared decision-making with patients, creation of multidisciplinary aortic teams, lower diameter thresholds for surgery in certain situations, and increased testing for patients with heritable aortic diseases. In addition to briefly reviewing basics of aortic diseases, the authors discuss changes to guidelines that are especially relevant to perioperative care.

The Year in Cardiothoracic Transplant Anesthesia: Selected Highlights From 2021 Part II: Cardiac Transplantation.

This article spotlights the research highlights of this year that specifically pertain to the specialty of anesthesia for heart transplantation. This includes the research on recent developments in the selection and optimization of donors and recipients, including the use of donation after cardiorespiratory death and extended criteria donors, the use of mechanical circulatory support and nonmechanical circulatory support as bridges to transplantation, the effect of COVID-19 on heart transplantation candidates and recipients, and new advances in the perioperative management of these patients, including the use of echocardiography and postoperative outcomes, focusing on renal and cerebral outcomes.

High ploidy large cytoplasmic megakaryocytes are hematopoietic stem cells regulators and essential for platelet production.

Megakaryocytes (MK) generate platelets. Recently, we and others, have reported MK also regulate hematopoietic stem cells (HSC). Here we show high ploidy large cytoplasmic megakaryocytes (LCM) are critical negative regulators of HSC and critical for platelet formation. Using a mouse knockout model (Pf4-Srsf3Δ/Δ) with normal MK numbers, but essentially devoid of LCM, we demonstrate a pronounced increase in BM HSC concurrent with endogenous mobilization and extramedullary hematopoiesis. Severe thrombocytopenia is observed in animals with diminished LCM, although there is no change in MK ploidy distribution, uncoupling endoreduplication and platelet production. When HSC isolated from a microenvironment essentially devoid of LCM reconstitute hematopoiesis in lethally irradiated mice, the absence of LCM increases HSC in BM, blood and spleen, and the recapitulation of thrombocytopenia. In contrast, following a competitive transplant using minimal numbers of WT HSC together with HSC from a microenvironment with diminished LCM, sufficient WT HSC-generated LCM regulates a normal HSC pool and prevents thrombocytopenia. Importantly, LCM are conserved in humans.

CO2-Responsive Low Molecular Weight Polymer with High Osmotic Pressure as a Draw Solute for Forward Osmosis.

A key challenge in the development of forward osmosis (FO) technology is to identify a suitable draw solute that can generate a large osmotic pressure with favorable water flux while being easy to recover after the FO process with a minimum of energy expenditure. While the CO2- and thermo-responsive linear poly(N,N-dimethylallylamine) polymer (l-PDMAAm) has been reported as a promising draw agent for forward osmosis desalination, the draw solutions sufficiently concentrated to have high osmotic pressure were too viscous to be usable in industrial operations. We now compare the viscosities and osmotic pressures of solutions of these polymers at low and high molecular weights and with/without branching. The best combination of high osmotic pressures with low viscosity can be obtained by using low molecular weights rather than branching. Aqueous solutions of the synthesized polymer showed a high osmotic pressure of 170 bar under CO2 (πCO2) at 50 wt% loading, generating a high water flux against NaCl feed solutions in the FO process. Under air, however, the same polymer showed a low osmotic pressure and a cloud point between 26 and 33 °C (depending on concentration), which facilitates the recovery of the polymer after it has been used as a draw agent in the FO process upon removal of CO2 from the system.

2022 ISFM/AAFP Cat Friendly Veterinary Environment Guidelines.

PRACTICAL RELEVANCE: The '2022 ISFM/AAFP Cat Friendly Veterinary Environment Guidelines' (hereafter the 'Cat Friendly Veterinary Environment Guidelines') describe how the veterinary clinic environment can be manipulated to minimise feline patient distress. Many components of a veterinary clinic visit or stay may result in negative experiences for cats. However, much can be done to improve a cat's experience by making the veterinary clinic more cat friendly. Exposure to other cats and other species can be reduced, and adjustments made with consideration of the feline senses and species-specific behaviour. Caregivers can prepare cats for a clinic visit with appropriate advice. Waiting rooms, examination rooms, hospital wards and other clinic areas can be designed and altered to reduce stress and hence encourage positive emotions. Changes need not be structural or expensive in order to be effective and make a difference to the cats and, in turn, to cat caregivers and the veterinary team. Moreover, by improving the all-round experience at the veterinary clinic, there are positive effects on preventive healthcare, identification of and recovery from illness, and compliance with treatment. CLINICAL CHALLENGES: Good feline healthcare necessitates visiting the veterinary clinic, which, simply by being outside of a cat's territory and familiar surroundings, may lead to negative experiences. Such experiences can trigger negative (protective) emotions and associated physiological stress, which can result in misleading clinical findings, patient distress, prolonged recovery from illness, further difficulties with handling at subsequent visits and potential veterinary personnel injury. There may be a mistaken belief that veterinary clinics must undergo significant renovation or building work to become cat friendly, and that, if species cannot be separated, then clinics cannot improve their care of cats. These Guidelines aim to dispel any such misconceptions and provide detailed practical advice. EVIDENCE BASE: These Guidelines have been created by a Task Force of experts convened by the International Society of Feline Medicine and American Association of Feline Practitioners, based on an extensive literature review and, where evidence is lacking, the authors' experience. Endorsements: These Guidelines have been endorsed by a number of groups and organisations, as detailed on page 1161 and at icatcare.org/cat-friendly-guidelines and catvets.com/environment.

2022 AAFP/ISFM Cat Friendly Veterinary Interaction Guidelines: Approach and Handling Techniques.

PRACTICAL RELEVANCE: The '2022 AAFP/ISFM Cat Friendly Veterinary Interaction Guidelines: Approach and Handling Techniques' (hereafter the 'Cat Friendly Veterinary Interaction Guidelines') support veterinary professionals with feline interactions and handling to reduce the impact of fear and other protective (negative) emotions, in so doing enhancing feline welfare and In implementing these Guidelines, team satisfaction and cat caregiver confidence in the veterinary team will increase as the result of efficient examinations, better experience, more reliable diagnostic testing and improved feline wellbeing. Veterinary professionals will learn the importance of understanding and appropriately responding to the current emotional state of the cat and tailoring each visit to the individual. CLINICAL CHALLENGES: Cats have evolved with emotions and behaviors that are necessary for their survival as both a predator and prey species. A clinical setting and the required examinations and procedures to meet their physical health needs can result in behavioral responses to protective emotions. Cat friendly interactions require understanding, interpreting and appropriately responding to cats' emotional states and giving them a perceived sense of control while performing the required assessment. EVIDENCE BASE: These Guidelines have been created by a Task Force of experts convened by the American Association of Feline Practitioners and the International Society of Feline Medicine, based on an extensive literature review and, where evidence is lacking, the authors' experience. ENDORSEMENTS: These Guidelines have been endorsed by a number of groups and organizations, as detailed on page 1127 and at catvets.com/interactions and icatcare.org/cat-friendly-guidelines.

Overweight, obesity and excessive weight gain in pregnancy as risk factors for adverse pregnancy outcomes: A narrative review.

The global prevalence of overweight and obesity in pregnancy is rising and this represents a significant challenge for the management of pregnancy and delivery. Women who have a pre-pregnancy body mass index greater than 25 kg m-2 are more likely than those with a body mass index in the ideal range (20-24.99 kg m-2 ) to have problems conceiving a child and are at greater risk of miscarriage and stillbirth. All pregnancy complications are more likely with overweight, obesity and excessive gestational weight gain, including those that pose a significant threat to the lives of mothers and babies. Labour complications arise more often when pregnancies are complicated by overweight and obesity. Pregnancy is a stage of life when women have greater openness to messages about their lifestyle and health. It is also a time when they come into greater contact with health professionals. Currently management of pregnancy weight gain and the impact of overweight tends to be poor, although a number of research studies have demonstrated that appropriate interventions based around dietary change can be effective in controlling weight gain and reducing the risk of pregnancy complications. The development of individualised and flexible plans for avoiding adverse outcomes of obesity in pregnancy will require investment in training of health professionals and better integration into normal antenatal care.

The RNA-binding protein SRSF3 has an essential role in megakaryocyte maturation and platelet production.

RNA processing is increasingly recognized as a critical control point in the regulation of different hematopoietic lineages including megakaryocytes responsible for the production of platelets. Platelets are anucleate cytoplasts that contain a rich repertoire of RNAs encoding proteins with essential platelet functions derived from the parent megakaryocyte. It is largely unknown how RNA binding proteins contribute to the development and functions of megakaryocytes and platelets. We show that serine-arginine-rich splicing factor 3 (SRSF3) is essential for megakaryocyte maturation and generation of functional platelets. Megakaryocyte-specific deletion of Srsf3 in mice led to macrothrombocytopenia characterized by megakaryocyte maturation arrest, dramatically reduced platelet counts, and abnormally large functionally compromised platelets. SRSF3 deficient megakaryocytes failed to reprogram their transcriptome during maturation and to load platelets with RNAs required for normal platelet function. SRSF3 depletion led to nuclear accumulation of megakaryocyte mRNAs, demonstrating that SRSF3 deploys similar RNA regulatory mechanisms in megakaryocytes as in other cell types. Our study further suggests that SRSF3 plays a role in sorting cytoplasmic megakaryocyte RNAs into platelets and demonstrates how SRSF3-mediated RNA processing forms a central part of megakaryocyte gene regulation. Understanding SRSF3 functions in megakaryocytes and platelets provides key insights into normal thrombopoiesis and platelet pathologies as SRSF3 RNA targets in megakaryocytes are associated with platelet diseases.