Validation of the Integrated Palliative Care Outcome Scale (IPOS) in adults with cystic fibrosis.

BACKGROUND: A primary palliative care model for cystic fibrosis (CF) recommends using the Integrated Palliative Care Outcome Scale (IPOS) for screening. Validation of the IPOS is needed. METHODS: This secondary analysis utilized baseline data from a multisite trial of the palliative care model, Improving Life with CF. Adults with CF completed the IPOS, the Memorial Symptom Assessment Scale-CF (MSAS-CF), the CF Questionnaire-Revised (CFQ-R), the Patient Health Questionnaire (PHQ-8), the Generalized Anxiety Disorder (GAD-7), and the Perceived Stress Scale (PSS). IPOS structure was assessed using Cronbach α coefficients and a factor analysis. Construct validity was evaluated through bivariate relationships between IPOS scores and other questionnaire scores, and linear regressions assessing the extent to which the IPOS explains variance in quality-of-life domains. RESULTS: The sample comprised 256 adults with complete IPOS data. α coefficients were .86 for the IPOS total score, .81 for the Physical Symptoms subscale, .79 for the Emotional Symptoms subscale, and .63 for the Communication/Practical Issues subscale. A two-component factor structure best aligned with the current subscales. IPOS scores were significantly associated with other measures; associations with MSAS-CF and CFQ-R subscales differentiated the IPOS Physical and Emotional subscales. The IPOS total score provided unique information about the variance in the CFQ-R Physical Functioning and Respiratory Symptoms domain scores. CONCLUSIONS: In adults with CF, the IPOS has acceptable internal consistency and there is evidence of construct validity. These findings support adoption of the IPOS in the primary palliative care model for CF.

IN SEARCH OF MOUSE MODELS FOR EXFOLIATION SYNDROME.

PURPOSE: Exfoliation syndrome (XFS) is a systemic connective tissue disorder with elusive pathophysiology. We hypothesize that a mouse model with elastic fiber defects caused by lack of lysyl oxidase like 1 (LOXL1 encoded by Loxl1), combined with microfibril deficiency due to Fbn1 mutation (encoding fibrillin-1, Fbn1C1041G/+) will display ocular and systemic phenotypes of XFS. METHODS: Loxl1-/- was crossed with Fbn1C1041G/+ to create double mutant (dbm) mice. Intraocular pressure (IOP), visual acuity (VA), electroretinogram (ERG) and biometry were characterized in 4 genotypes (wt, Fbn1C1041G/+, Loxl1-/-, dbm) at 16 weeks old. Optic nerve area was measured by ImageJ and axon counting was achieved by AxonJ. Deep whole-body phenotyping was performed in wt and dbm mice. Two-tailed Student's t-test was used for statistical analysis. RESULTS: There was no difference in IOP between the 4 genotypes. VA was significantly reduced only in dbm mice. The majority of biometric parameters showed significant differences in all 3 mutant genotypes compared to wt, and dbm had exacerbated anomalies compared to single mutants. Dbm mice showed reduced retinal function and significantly enlarged ON area when compared with wt. Dbm mice exhibited severe systemic phenotypes related to abnormal elastic fibers, such as pelvic organ prolapse, cardiovascular and pulmonary abnormalities. CONCLUSIONS: Ocular and systemic findings in dbm mice support functional overlap between fibrillin-1 and LOXL1, two prominent components of exfoliation material. Although no elevated IOP or reduction of axon numbers was detected in dbm mice at 16-week-old, their reduced retinal function and enlarged ON area indicate early retinal ganglion cell dysfunction. Dbm mice also provide insight on the link between XFS and systemic diseases in humans.

Working Conditions, Worker Rights, and Managerial Domination During the COVID-19 Pandemic: Assessing Their Toll on Precariously Employed Workers and Family Well-Being.

Precarious Employment (PE) is characterized by job, income, and benefit insecurities. Studies surrounding PE and well-being have been predominantly quantitative, leaving a gap in rich descriptions of employment experiences. We recruited a sample of 40 adults aged 25-55 who were involved in PE during the beginning of the COVID-19 pandemic or lost employment due to the pandemic. Semi-structured interviews were administered. Employment and income insecurities were common and had negative impacts on the well-being of participants and their families. Uncertainty about future employment prospects and job and income loss resulted in chronic distress. Other insecurities-access to benefits, violation of worker rights, worker safety-was also reported as impacting well-being. The COVID-19 pandemic deepened insecurities, hardships, and distress among workers with PE conditions. Given the myriad insecurities experienced by those engaged in PE, the focus of precarious work research should also include working conditions, violation of worker rights, and managerial domination.

The Functional Significance of High Cysteine Content in Eye Lens γ-Crystallins.

Cataract disease is strongly associated with progressively accumulating oxidative damage to the extremely long-lived crystallin proteins of the lens. Cysteine oxidation affects crystallin folding, interactions, and light-scattering aggregation especially strongly due to the formation of disulfide bridges. Minimizing crystallin aggregation is crucial for lifelong lens transparency, so one might expect the ubiquitous lens crystallin superfamilies (α and ßγ) to contain little cysteine. Yet, the Cys content of γ-crystallins is well above the average for human proteins. We review literature relevant to this longstanding puzzle and take advantage of expanding genomic databases and improved machine learning tools for protein structure prediction to investigate it further. We observe remarkably low Cys conservation in the ßγ-crystallin superfamily; however, in γ-crystallin, the spatial positioning of Cys residues is clearly fine-tuned by evolution. We propose that the requirements of long-term lens transparency and high lens optical power impose competing evolutionary pressures on lens ßγ-crystallins, leading to distinct adaptations: high Cys content in γ-crystallins but low in ßB-crystallins. Aquatic species need more powerful lenses than terrestrial ones, which explains the high methionine content of many fish γ- (and even ß-) crystallins. Finally, we discuss synergies between sulfur-containing and aromatic residues in crystallins and suggest future experimental directions.

Interleukin 6 at menstruation promotes the proliferation and self-renewal of endometrial mesenchymal stromal/stem cells through the WNT/ß-catenin signaling pathway.

Background: At menstruation, the functional layer of the human endometrium sheds off due to the trigger of the release of inflammatory factors, including interleukin 6 (IL-6), as a result of a sharp decline in progesterone levels, leading to tissue breakdown and bleeding. The endometrial mesenchymal stem-like cells (CD140b+CD146+ eMSC) located in the basalis are responsible for the cyclical regeneration of the endometrium after menstruation. Endometrial cells from the menstruation phase have been proven to secrete a higher amount of IL-6 and further enhance the self-renewal and clonogenic activity of eMSC. However, the IL-6-responsive mechanism remains unknown. Thus, we hypothesized that IL-6 secreted from niche cells during menstruation regulates the proliferation and self-renewal of eMSC through the WNT/ß-catenin signaling pathway. Methods: In this study, the content of IL-6 across the menstrual phases was first evaluated. Coexpression of stem cell markers (CD140b and CD146) with interleukin 6 receptor (IL-6R) was confirmed by immunofluorescent staining. In vitro functional assays were conducted to investigate the effect of IL-6 on the cell activities of eMSC, and the therapeutic role of these IL-6- and WNT5A-pretreated eMSC on the repair of injured endometrium was observed using an established mouse model. Results: The endometrial cells secrete a high amount of IL-6 under hypoxic conditions, which mimic the physiological microenvironment in the menstruation phase. Also, the expression of IL-6 receptors was confirmed in our eMSC, indicating their capacity to respond to IL-6 in the microenvironment. Exogenous IL-6 can significantly enhance the self-renewal, proliferation, and migrating capacity of eMSC. Activation of the WNT/ß-catenin signaling pathway was observed upon IL-6 treatment, while suppression of the WNT/ß-catenin signaling impaired the stimulatory role of IL-6 on eMSC activities. IL-6- and WNT5A-pretreated eMSC showed better performance during the regeneration of the injured mouse endometrium. Conclusion: We demonstrate that the high level of IL-6 produced by endometrial cells at menstruation can induce the stem cells in the human endometrium to proliferate and migrate through the activation of the WNT/ß-catenin pathway. Treatment of eMSC with IL-6 and WNT5A might enhance their therapeutic potential in the regeneration of injured endometrium.

Marginal bone loss in ball versus locator attachments in implant-retained overdentures: systematic review and meta-analysis.

OBJECTIVES: This systematic review compares the impact of ball and locator attachments on marginal bone loss in implant-retained overdentures in completely edentulous patients. METHOD AND MATERIALS: Following PRISMA guidelines, health science librarians completed literature searches from inception to 17 March 2023 in seven databases. There were 15,686 items exported to EndNote from Embase.com, CINAHL (EBSCO), Cochrane Library, Ovid MEDLINE-ALL, PubMed, Scopus, and Web of Science. Hand-searching added four more articles. After deduplication, 6,756 items were screened for eligibility. Twenty-nine studies were assessed by full text, of which ten studies, involving 424 subjects, were included in the review. Risk of bias assessment was conducted using the Cochrane risk-of-bias tool and the Newcastle-Ottawa scale. A meta-analysis was performed to synthesize and analyze the collective data from the selected studies. RESULTS: The included studies used diverse methodologies, implant systems, and loading protocols. Most studies reported no significant difference in marginal bone loss between ball and locator attachments. The meta-analysis revealed high heterogeneity. CONCLUSION: The results of this systematic review suggest that ball and locator attachments exhibit similar performance in terms of marginal bone loss in implant-retained overdentures. However, the limited number, risk of bias, and heterogeneity of studies highlight the need for standardized research designs and larger sample sizes in future investigations to draw more definitive conclusions.

Twelve tips for supporting medical learners through high-stakes assessment challenges.

Learners across the medical education continuum will encounter numerous high-stakes exams and assessments. Effectively preparing for and performing well on these types of assessments can be challenging for learners for a wide variety of reasons. It is imperative that medical educators provide appropriate support for learners who experience challenges with high-stakes exams, particularly given the complexity of factors like life circumstances of individual learners and the significance of these assessments for career advancement/progression. Grouped into areas including educator mindset, information-gathering, and developing and executing a study plan, the following 12 tips will help medical educators be better prepared to meaningfully support learners in need of assessment remediation and guidance.

Fidelity in Academic Global Surgery and Research: Incorporating Trustworthiness in the Development of Research Partnerships, Infrastructure, and Policy.

Academic global surgery consists of collaborative partnerships that address surgical inequities through research, training, education, advocacy, and diplomacy. It has been characterized by increased scholastic production through global surgery publications, dedicated global surgery sessions within scientific conferences, global surgery-specific research grants, database development to support global surgery research, global surgery research fellowships, and global surgery-based academic promotion paradigms. The increased emphasis on global surgery research has been accompanied by multiple ethical challenges. This article reviews critical ethical dilemmas presented by global surgery research efforts and proposes interventions on the partnership, infrastructural, and policy levels to enhance fidelity within research partnerships.

Early Parenting Interactions and First-Time Mothers' Postnatal Depression and Parental Competence.

Objectives: Schema Therapy, an approach that integrates cognitive-behavioural and attachment principles, helps us understand the impact of early interactions with caregivers on adult mental health. These early interactions can be assessed through Schema Therapy-informed tools; however, these tools have yet to be used with a postnatal population, which represents a period of vulnerability for new mothers. Therefore, the present study aimed to evaluate the impact of positive and negative early parenting interactions on a first-time mother's mental health and her sense of competence during the postnatal period, using recently revised and newly developed Schema Therapy-informed tools. Design: This is a cross-sectional study. Method: First-time mothers (N = 220) participated in an online survey within 12 months post-birth. Participants completed the Positive Parenting Schema Inventory (PPSI), Young Parenting Inventory-Revised (YPI-R2), Edinburgh Postnatal Depression Scale (EPDS), and Parenting Sense of Competence (PSOC) scale. The data were analysed using hierarchical multiple regression and mediational analysis. Results: Negative early interactions with mothers and fathers led to greater postnatal depressive symptomology, while positive early interactions with mothers led to fewer postnatal depressive symptoms. Mediation analyses revealed that postnatal depressive symptoms mediated early parenting interactions and participants' sense of parenting competence as a new mother. Conclusions: The protective effects of positive early interactions with caregivers can help first-time mothers' postnatal emotional adjustment and their sense of competence through diminished postnatal depressive symptoms. However, the enduring effects of negative early interactions with caregivers can contribute to a first-time mother's risk of developing postnatal depression and negatively affect her sense of parental competence.

Enhanced Optic Nerve Expansion and Altered Ultrastructure of Elastic Fibers Induced by Lysyl Oxidase Inhibition in a Mouse Model of Marfan Syndrome.

Two major constituents of exfoliation material, fibrillin-1 and lysyl oxidase-like 1 (encoded by FBN1 and LOXL1), are implicated in exfoliation glaucoma, yet their individual contributions to ocular phenotype are minor. To test the hypothesis that a combination of FBN1 mutation and LOXL1 deficiency exacerbates ocular phenotypes, the pan-lysyl oxidase inhibitor ß-aminopropionitrile (BAPN) was used to treat adult wild-type (WT) mice and mice heterozygous for a missense mutation in Fbn1 (Fbn1C1041G/+) for 8 weeks and their eyes were examined. Although intraocular pressure did not change and exfoliation material was not detected in the eyes, BAPN treatment worsened optic nerve and axon expansion in Fbn1C1041G/+ mice, an early sign of axonal damage in rodent models of glaucoma. Disruption of elastic fibers was detected only in Fbn1C1041G/+ mice, which increased with BAPN treatment, as shown by histologic and immunohistochemical staining of the optic nerve pia mater. Transmission electron microscopy showed that Fbn1C1041G/+ mice had fewer microfibrils, smaller elastin cores, and a lower density of elastic fibers compared with WT mice in control groups. BAPN treatment led to elastin core expansion in both WT and Fbn1C1041G/+ mice, but an increase in the density of elastic fiber was confined to Fbn1C1041G/+ mice. LOX inhibition had a stronger effect on optic nerve and elastic fiber parameters in the context of Fbn1 mutation, indicating the Marfan mouse model with LOX inhibition warrants further investigation for exfoliation glaucoma pathogenesis.

Automated test apparatus for bench-testing the magnetic field homogeneity of NMR transceiver coils.

We describe an automated hands-off bench testing method for measuring the magnetic field profile of transceiver coils for nuclear magnetic resonance (NMR). The scattering parameter (S-parameter) data is measured using a portable network analyzer, and the results are automatically exported to a computer for plotting and viewing. This assay dramatically reduces the time needed to measure the magnetic field (B1) homogeneity profile of a transceiver coil while also improving accuracy relative to manual operation. Here, we demonstrate the method on a saddle coil of a solution-state NMR probe in comparison to profiles obtained using NMR spectroscopy measurements. We also measure the axial and radial homogeneity of a variable-pitch solenoid.

Evolving concepts in margin strategies and adaptive radiotherapy for glioblastoma: A new future is on the horizon.

Chemoradiotherapy is the standard treatment after maximal safe resection for glioblastoma (GBM). Despite advances in molecular profiling, surgical techniques, and neuro-imaging, there have been no major breakthroughs in radiotherapy (RT) volumes in decades. Although the majority of recurrences occur within the original gross tumor volume (GTV), treatment of a clinical target volume (CTV) ranging from 1.5 to 3.0 cm beyond the GTV remains the standard of care. Over the past 15 years, the incorporation of standard and functional MRI sequences into the treatment workflow has become a routine practice with increasing adoption of MR simulators, and new integrated MR-Linac technologies allowing for daily pre-, intra- and post-treatment MR imaging. There is now unprecedented ability to understand the tumor dynamics and biology of GBM during RT, and safe CTV margin reduction is being investigated with the goal of improving the therapeutic ratio. The purpose of this review is to discuss margin strategies and the potential for adaptive RT for GBM, with a focus on the challenges and opportunities associated with both online and offline adaptive workflows. Lastly, opportunities to biologically guide adaptive RT using non-invasive imaging biomarkers and the potential to define appropriate volumes for dose modification will be discussed.

Clinical Outcomes at 8-16 Weeks After Upadacitinib Initiation for Acute Severe Ulcerative Colitis: A Case Series in the United States.

In 9 patients hospitalized for acute severe ulcerative colitis, 8 were successfully discharged without the need for colectomy. Six of 7 patients with sufficient follow-up achieved steroid-free clinical remission at 8 to 16 weeks, and 1 of 2 patients achieved endoscopic response.

Mental health facilities with eating disorder treatment programs and substance use disorder treatment in the United States.

Eating disorders (EDs) and substance use disorders (SUDs) often co-occur. However, not all providers that treat persons with an ED provide SUD treatment. Using the National Mental Health Services Survey, this study examined 1,387 ED treatment providers in the U.S. Facilities were categorized according to whether they provided SUD treatment. Differences based on facilities' profit status, available treatment settings, payment options, and treatment services were examined. Most ED facilities in the sample offered SUD treatment services (67.2%). Differences in proportions of the facility type, availability of outpatient treatment, sliding fee scale payment option, whether the facility had a program for individuals with co-occurring mental health and SUD, couples/family therapy, dual disorders treatment, and if the facility provided telemedicine/telehealth were identified. Although most facilities in this sample offered SUD services, more should be done to increase such facilities' capacity to provide treatment for co-occurring ED and SUD nationwide.

Nearly 70% of all ED treatment facilities reported offering SUD treatment.Geographic disparities in these integrated services exist.Eighty-six percent of these facilities had outpatient treatment.

Local anesthesia versus general anesthesia for surgical drainage of chronic subdural hematoma: a systematic review and meta-analysis.

PURPOSE: The optimal anesthetic technique for surgical drainage of chronic subdural hematoma (CSDH) is still uncertain. We performed this systematic review and meta-analysis to determine if local anesthesia with or without sedation (LA) or general anesthesia (GA) results in better outcomes for surgical drainage of CSDH. METHODS: We searched PubMed, EMBASE, Scopus, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for randomized controlled trials (RCTs) and prospective or retrospective studies that compared GA vs LA for adult patients undergoing surgical drainage of CSDH and reported at least one outcome of interest. Primary outcomes of interest included total duration of surgery, recurrence rate, and length of hospital stay (LOS). Secondary outcomes included intraoperative adverse events, postoperative complications, and postoperative mortality. RESULTS: Eight studies (1,542 patients; 926 LA; 616 GA) were included-two were RCTs and six were observational studies. Pooling the estimates of all available studies, we found that LA was associated with a decreased mean LOS by about two days (95% confidence interval [CI], -3.47 to -0.77; P = 0.01; low certainty of evidence) as well as a lower risk of postoperative complications (odds ratio, 0.31; 95% CI, 0.17 to 0.58; P = 0.004; very low certainty of evidence). There was no significant difference in terms of duration of surgery, recurrence rate, intraoperative adverse events, or mortality. The quality of the observational studies was poor to fair, largely because of heterogeneity among the studies. Among the RCTs, one had a low risk of bias and one was deemed to be at high risk of bias. CONCLUSIONS: Local anesthesia with/without sedation for surgical drainage of CSDH may be associated with a shorter LOS, and lower postoperative complications. As most of our included studies were observational in nature, our results should be interpreted as summaries of unadjusted group comparisons. In view of the low certainty of evidence, higher quality evidence is required to corroborate these findings. STUDY REGISTRATION: PROSPERO (CRD42022333388); first submitted 1 June 2022.

RéSUMé: OBJECTIF: La technique anesthésique optimale pour le drainage chirurgical de l'hématome sous-dural chronique (HSDC) demeure incertaine. Nous avons réalisé cette revue systématique et méta-analyse pour déterminer si l'anesthésie locale (AL) avec ou sans sédation ou l'anesthésie générale (AG) entraînait de meilleurs devenirs suite à un drainage chirurgical de l'HSDC. MéTHODE: Nous avons effectué des recherches dans les bases de données PubMed, EMBASE, Scopus, le registre central Cochrane des études contrôlées et ClinicalTrials.gov afin d'en extraire les études randomisées contrôlées (ERC) et les études prospectives ou rétrospectives qui comparaient l'AG à l'AL chez une patientèle adulte bénéficiant d'un drainage chirurgical de l'HSDC et qui rapportaient au moins un résultat d'intérêt. Les critères d'évaluation principaux d'intérêt comprenaient la durée totale de la chirurgie, le taux de récidive et la durée du séjour à l'hôpital. Les critères d'évaluation secondaires comprenaient les événements indésirables peropératoires, les complications postopératoires et la mortalité postopératoire. RéSULTATS: Huit études (1542 patients, 926 AL, 616 AG) ont été incluses, dont deux ERC et six études observationnelles. En regroupant les estimations de toutes les études disponibles, nous avons constaté que l'AL était associée à une diminution de la durée moyenne de séjour d'environ deux jours (intervalle de confiance [IC] à 95 %, −3,47 à −0,77; P = 0,01; faible certitude des données probantes) ainsi qu'à un risque plus faible de complications postopératoires (rapport de cotes, 0,31; IC 95 %, 0,17 à 0,58; P = 0,004; très faible certitude des données probantes). Il n'y avait pas de différence significative en termes de durée de la chirurgie, ni de taux de récidive, d'événements indésirables peropératoires ou de mortalité. La qualité des études observationnelles était médiocre à passable, en grande partie en raison de l'hétérogénéité entre les études. Parmi les ERC, l'une présentait un faible risque de biais et l'autre a été considérée comme présentant un risque élevé de biais. CONCLUSION: L'anesthésie locale avec ou sans sédation pour le drainage chirurgical de l'HSDC peut être associée à une durée de séjour hospitalier plus courte et à des complications postopératoires plus faibles. Étant donné que la plupart des études incluses étaient de nature observationnelle, nos résultats doivent être interprétés comme des résumés de comparaisons de groupes non ajustées. Compte tenu de la faible certitude des données probantes, des données de meilleure qualité sont nécessaires pour corroborer ces conclusions. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42022333388); soumis pour la première fois le 1er juin 2022.

Synchronous retreat of Thwaites and Pine Island glaciers in response to external forcings in the presatellite era.

Today, relatively warm Circumpolar Deep Water is melting Thwaites Glacier at the base of its ice shelf and at the grounding zone, contributing to significant ice retreat. Accelerating ice loss has been observed since the 1970s; however, it is unclear when this phase of significant melting initiated. We analyzed the marine sedimentary record to reconstruct Thwaites Glacier's history from the early Holocene to present. Marine geophysical surveys were carried out along the floating ice-shelf margin to identify core locations from various geomorphic settings. We use sedimentological data and physical properties to define sedimentary facies at seven core sites. Glaciomarine sediment deposits reveal that the grounded ice in the Amundsen Sea Embayment had already retreated to within ~45 km of the modern grounding zone prior to ca. 9,400 y ago. Sediments deposited within the past 100+ y record abrupt changes in environmental conditions. On seafloor highs, these shifts document ice-shelf thinning initiating at least as early as the 1940s. Sediments recovered from deep basins reflect a transition from ice proximal to slightly more distal conditions, suggesting ongoing grounding-zone retreat since the 1950s. The timing of ice-shelf unpinning from the seafloor for Thwaites Glacier coincides with similar records from neighboring Pine Island Glacier. Our work provides robust new evidence that glacier retreat in the Amundsen Sea was initiated in the mid-twentieth century, likely associated with climate variability.

Granulocytic myeloid-derived suppressor cell activity during biofilm infection is regulated by a glycolysis/HIF1a axis.

Staphylococcus aureus is a leading cause of biofilm-associated prosthetic joint infection (PJI). A primary contributor to infection chronicity is an expansion of granulocytic myeloid-derived suppressor cells (G-MDSCs), which are critical for orchestrating the antiinflammatory biofilm milieu. Single-cell sequencing and bioinformatic metabolic algorithms were used to explore the link between G-MDSC metabolism and S. aureus PJI outcome. Glycolysis and the hypoxia response through HIF1a were significantly enriched in G-MDSCs. Interfering with both pathways in vivo, using a 2-deoxyglucose nanopreparation and granulocyte-targeted Hif1a conditional KO mice, respectively, attenuated G-MDSC-mediated immunosuppression and reduced bacterial burden in a mouse model of S. aureus PJI. In addition, single-cell RNA-Seq (scRNA-Seq) analysis of granulocytes from PJI patients also showed an enrichment in glycolysis and hypoxia-response genes. These findings support the importance of a glycolysis/HIF1a axis in promoting G-MDSC antiinflammatory activity and biofilm persistence during PJI.

Endometrial mesenchymal stromal/stem cells improve regeneration of injured endometrium in mice.

BACKGROUND: The monthly regeneration of human endometrial tissue is maintained by the presence of human endometrial mesenchymal stromal/stem cells (eMSC), a cell population co-expressing the perivascular markers CD140b and CD146. Endometrial regeneration is impaired in the presence of intrauterine adhesions, leading to infertility, recurrent pregnancy loss and placental abnormalities. Several types of somatic stem cells have been used to repair the damaged endometrium in animal models, reporting successful pregnancy. However, the ability of endometrial stem cells to repair the damaged endometrium remains unknown. METHODS: Electrocoagulation was applied to the left uterine horn of NOD/SCID mice causing endometrial injury. Human eMSC or PBS was then injected into the left injured horn while the right normal horn served as controls. Mice were sacrificed at different timepoints (Day 3, 7 and 14) and the endometrial morphological changes as well as the degree of endometrial injury and repair were observed by histological staining. Gene expression of various inflammatory markers was assessed using qPCR. The functionality of the repaired endometrium was evaluated by fertility test. RESULTS: Human eMSC successfully incorporated into the injured uterine horn, which displayed significant morphological restoration. Also, endometrium in the eMSC group showed better cell proliferation and glands formation than the PBS group. Although the number of blood vessels were similar between the two groups, gene expression of VEGF-α significantly increased in the eMSC group. Moreover, eMSC had a positive impact on the regeneration of both stromal and epithelial components of the mouse endometrium, indicated by significantly higher vimentin and CK19 protein expression. Reduced endometrial fibrosis and down-regulation of fibrosis markers were also observed in the eMSC group. The eMSC group had a significantly higher gene expression of anti-inflammatory factor Il-10 and lower mRNA level of pro-inflammatory factors Ifng and Il-2, indicating the role of eMSC in regulation of inflammatory reactions. The eMSC group showed higher implantation sites than the PBS group, suggesting better endometrial receptivity with the presence of newly emerged endometrial lining. CONCLUSIONS: Our findings suggest eMSC improves regeneration of injured endometrium in mice.

Feasibility and Clinical Utility of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified in Research Germline Sequencing: A Prospective Interventional Study.

PURPOSE: Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant secondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician. METHODS: This prospective, interventional cohort study enrolled Total Cancer Care participants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic analysis in a Clinical Laboratory Improvement Amendments-certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College of Medical Genomics and Genetics SF v2.0 genes. After a protocol modification in consenting patients, the MTB reported PGVs to treating oncology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing. RESULTS: Of the 781 enrolled participants, 32 (4.1%) harbored cancer predisposition PGVs, 24 (3.1%) were heterozygous carriers of an autosomal recessive cancer predisposition syndrome, and 14 (1.8%) had other hereditary disease PGVs. Guideline-directed testing would have missed 37.5% (12/32) of the inherited cancer predisposition PGVs, which included BRCA1, BRCA2, MSH6, SDHAF2, SDHB, and TP53 variants. Three hundred fifteen participants consented to reporting results; results for all living patients were reported to the clinical team with half referred to a licensed genetic counselor. There was concordance between all research variants identified in patients (n = 9) who underwent clinical confirmatory sequencing. CONCLUSION: MTB reporting of research-grade germline sequencing to the clinical oncology team is feasible. Over a third of PGVs identified using a universal testing strategy would have been missed by guideline-based approach, suggesting a role for expanding germline testing.