Characterization of m6A Modifiers and RNA Modifications in Uterine Fibroids.

Uterine leiomyoma or fibroids are prevalent noncancerous tumors of the uterine muscle layer, yet their origin and development remain poorly understood. We analyzed RNA expression profiles of 15 epigenetic mediators in uterine fibroids compared to myometrium using publicly available RNA sequencing (RNA-seq) data. To validate our findings, we performed RT-qPCR on a separate cohort of uterine fibroids targeting these modifiers confirming our RNA-seq data. We then examined protein profiles of key N6-methyladenosine (m6A) modifiers in fibroids and their matched myometrium, showing no significant differences in concordance with our RNA expression profiles. To determine RNA modification abundance, mRNA and small RNA from fibroids and matched myometrium were analyzed by ultra-high performance liquid chromatography-mass spectrometry identifying prevalent m6A and 11 other known modifiers. However, no aberrant expression in fibroids was detected. We then mined a previously published dataset and identified differential expression of m6A modifiers that were specific to fibroid genetic subtype. Our analysis also identified m6A consensus motifs on genes previously identified to be dysregulated in uterine fibroids. Overall, using state-of-the-art mass spectrometry, RNA expression, and protein profiles, we characterized and identified differentially expressed m6A modifiers in relation to driver mutations. Despite the use of several different approaches, we identified limited differential expression of RNA modifiers and associated modifications in uterine fibroids. However, considering the highly heterogenous genomic and cellular nature of fibroids, and the possible contribution of single molecule m6A modifications to fibroid pathology, there is a need for greater in-depth characterization of m6A marks and modifiers in a larger and diverse patient cohort.

Mexican consensus about surgical treatment in early-stage cervicouterine cancer.

Introduction: Cervical cancer is a public health problem in our country and worldwide. Less than 25% of cases are diagnosed in the early stages, where survival is more remarkable than 90% at five years. Here, we review surgical treatment in the early stages of cervical cancer. Methodology: A literature review was carried out in the MEDLINE database. The search was mainly limited to the English language, with priority given to systematic reviews with or without meta-analysis and randomized studies. However, only retrospective or observational evidence was found for some topics. Results: The standard treatment for early-stage cervical cancer is hysterectomy, and its radical nature will depend on the tumor size, lymphovascular permeation, and tumor-specific prognostic factors. Furthermore, the type of surgery (hysterectomy or trachelectomy) will rely on the patient's desire to preserve fertility. Nodal evaluation is indicated as part of the treatment from stage IAI with PLV. However, the sentinel lymph node is more relevant in the treatment. The incidental finding of cervical cancer after a hysterectomy requires a multidisciplinary evaluation to determine the therapeutic approach. Less radical surgery has been described as oncologically safe in low-risk groups. Conclusion: Surgical treatment in its early stages has evolved in recent decades, making it more individualized and seeking less morbidity in patients without compromising their survival.

Autistic adults in China and the Netherlands: Proxy-reported community integration and life satisfaction.

LAY ABSTRACT: Even though there are about 10 million Chinese autistic individuals, we know little about autistic adults in China. This study examined how well young autistic adults in China integrate into their communities (such as having a job, living independently and having friends) and how satisfied they are with their lives as reported by their caregivers. We compared them to autistic adults with similar characteristics (such as high support needs) from the Netherlands. We included 99 autistic adults in China and 109 in the Netherlands (18-30 years). In both countries, autistic adults were reported to have a hard time fitting into their communities. They often had no work, did not live on their own and had few close friends. Also, in both countries, caregivers reported that autistic adults felt low satisfaction with their life. Chinese adults were less satisfied with their life than Dutch adults, as indicated by their caregivers. This could be because of a lack of support for autistic adults in China, higher parental stress in Chinese caregivers, or general cross-country differences in happiness. Only in the Dutch group, younger compared with older adults fitted better into their communities, and adults without additional psychiatric conditions were reported to have higher life satisfaction. Country was a significant predictor of independent living only, with Dutch participants more likely living in care facilities than Chinese participants. In conclusion, our study shows that autistic adults with high support needs generally face similar challenges in both China and the Netherlands.

Lesions to the mediodorsal thalamus, but not orbitofrontal cortex, enhance volatility beliefs linked to paranoia.

Beliefs-attitudes toward some state of the environment-guide action selection and should be robust to variability but sensitive to meaningful change. Beliefs about volatility (expectation of change) are associated with paranoia in humans, but the brain regions responsible for volatility beliefs remain unknown. The orbitofrontal cortex (OFC) is central to adaptive behavior, whereas the magnocellular mediodorsal thalamus (MDmc) is essential for arbitrating between perceptions and action policies. We assessed belief updating in a three-choice probabilistic reversal learning task following excitotoxic lesions of the MDmc (n = 3) or OFC (n = 3) and compared performance with that of unoperated monkeys (n = 14). Computational analyses indicated a double dissociation: MDmc, but not OFC, lesions were associated with erratic switching behavior and heightened volatility belief (as in paranoia in humans), whereas OFC, but not MDmc, lesions were associated with increased lose-stay behavior and reward learning rates. Given the consilience across species and models, these results have implications for understanding paranoia.

A link between evolution and society fostering the UN sustainable development goals.

Given the multitude of challenges Earth is facing, sustainability science is of key importance to our continued existence. Evolution is the fundamental biological process underlying the origin of all biodiversity. This phylogenetic diversity fosters the resilience of ecosystems to environmental change, and provides numerous resources to society, and options for the future. Genetic diversity within species is also key to the ability of populations to evolve and adapt to environmental change. Yet, the value of evolutionary processes and the consequences of their impairment have not generally been considered in sustainability research. We argue that biological evolution is important for sustainability and that the concepts, theory, data, and methodological approaches used in evolutionary biology can, in crucial ways, contribute to achieving the UN Sustainable Development Goals (SDGs). We discuss how evolutionary principles are relevant to understanding, maintaining, and improving Nature Contributions to People (NCP) and how they contribute to the SDGs. We highlight specific applications of evolution, evolutionary theory, and evolutionary biology's diverse toolbox, grouped into four major routes through which evolution and evolutionary insights can impact sustainability. We argue that information on both within-species evolutionary potential and among-species phylogenetic diversity is necessary to predict population, community, and ecosystem responses to global change and to make informed decisions on sustainable production, health, and well-being. We provide examples of how evolutionary insights and the tools developed by evolutionary biology can not only inspire and enhance progress on the trajectory to sustainability, but also highlight some obstacles that hitherto seem to have impeded an efficient uptake of evolutionary insights in sustainability research and actions to sustain SDGs. We call for enhanced collaboration between sustainability science and evolutionary biology to understand how integrating these disciplines can help achieve the sustainable future envisioned by the UN SDGs.

Histoplasmosis Beyond Human Immunodeficiency Virus (HIV): Clinical Characteristics and Outcomes in a Non-HIV Population.

Histoplasmosis is an endemic and invasive mycosis caused by Histoplasma capsulatum. We conducted a retrospective study comparing immunosuppressed patients without human immunodeficiency virus (HIV) with a historical cohort of people with HIV and histoplasmosis. We included 199 patients with proven or probable histoplasmosis, of which 25.1% were people without HIV. Diabetes mellitus, chronic kidney disease, hematologic neoplasms, rheumatologic diseases, and transplantations were more frequent among people without HIV (P < .01). Forty-four percent of immunocompromised patients without HIV died within the first 6-week period following their diagnosis. A high suspicion index for histoplasmosis should be kept in immunosuppressed patients.

Fungal infections in patients after recovering from COVID-19: a systematic review.

Background and aims: The presence of fungal infections has been described in patients after recovering from COVID-19. This study aims to conduct a systematic review of studies that reported fungal infections (Mucor spp., Pneumocystis jirovecii, or Aspergillus spp.) in adults after recovering from COVID-19. Methods: We performed a systematic review through PubMed, Web of Science, OVID-Medline, Embase, and Scopus. The study selection process was performed independently and by at least two authors. We performed a risk of bias assessment using the Newcastle-Ottawa Scale for cohort and case-control studies, and the Joanna Briggs Institute's Checklists for Case Series and Case Reports. Results: The systematic search found 33 studies meeting all inclusion criteria. There was a total population of 774 participants, ranging from 21 to 87 years. From them, 746 developed a fungal infection. In 19 studies, Mucor spp. was reported as the main mycosis. In 10 studies, P. jirovecii was reported as the main mycosis. In seven studies, Aspergillus spp. was reported as the main mycosis. Regarding the quality assessment, 12 studies were classified as low risk of bias and the remaining studies as high risk of bias. Conclusion: Patients' clinical presentation and prognosis after recovering from COVID-19 with fungal infection differ from those reported patients with acute COVID-19 infection and those without COVID-19 infection.

Simultaneous rift-scale inflation of a deep crustal sill network in Afar, East Africa.

Decades of studies at divergent plate margins have revealed networks of magmatic sills at the crust-mantle boundary. However, a lack of direct observations of deep magma motion limits our understanding of magma inflow from the mantle into the lower crust and the mechanism of sill formation. Here, satellite geodesy reveals rift-scale deformation caused by magma inflow in the deep crust in the Afar rift (East Africa). Simultaneous inflation of four sills, laterally separated by 10s of km and at depths ranging 9-28 km, caused uplift across a ~ 100-km-wide zone, suggesting the sills are linked to a common mantle source. Our results show the supply of magma into the lower crust is temporally episodic, occurring across a network of sills. This process reflects inherent instability of melt migration through porous mantle flow and may be the fundamental process that builds the thick igneous crust beneath magmatic rifts and rifted margins globally.

A targeted CRISPR-Cas9 mediated F0 screen identifies genes involved in establishment of the enteric nervous system.

The vertebrate enteric nervous system (ENS) is a crucial network of enteric neurons and glia resident within the entire gastrointestinal tract (GI). Overseeing essential GI functions such as gut motility and water balance, the ENS serves as a pivotal bidirectional link in the gut-brain axis. During early development, the ENS is primarily derived from enteric neural crest cells (ENCCs). Disruptions to ENCC development, as seen in conditions like Hirschsprung disease (HSCR), lead to the absence of ENS in the GI, particularly in the colon. In this study, using zebrafish, we devised an in vivo F0 CRISPR-based screen employing a robust, rapid pipeline integrating single-cell RNA sequencing, CRISPR reverse genetics, and high-content imaging. Our findings unveil various genes, including those encoding opioid receptors, as possible regulators of ENS establishment. In addition, we present evidence that suggests opioid receptor involvement in the neurochemical coding of the larval ENS. In summary, our work presents a novel, efficient CRISPR screen targeting ENS development, facilitating the discovery of previously unknown genes, and increasing knowledge of nervous system construction.

Acetylcholinesterase inhibitors are ineffective in MuSK-antibody positive myasthenia gravis: Results of a study on 202 patients.

BACKGROUND: Myasthenia gravis (MG) with MuSK antibodies (MuSK-MG) represents a distinct subtype with different responses to treatments compared to patients with AChR antibodies, especially in terms of tolerance to acetylcholinesterase inhibitors (AChEI). However, AChEI are often used as first line symptomatic treatment in MuSK-MG, despite reports that they are poorly tolerated, seldom effective or even deleterious. METHODS: We analyzed demographic, clinical and therapeutic responses and side-effects in the large cohort of 202 MuSK-MG patients cared for at the MG Clinic of Azienda Ospedaliero-Universitaria Pisana. RESULTS: 165 patients had received AChEI at first evaluation. Only 7/165 patients (4.2%) reported an initial clinical benefit. Conversely, 76.9% of patients reported at least one side effect, most commonly neuromuscular hyperexcitability (68.4%), gastrointestinal (53.9%) and neurovegetative (35.8%) disturbances. 56 (33.9%) patients reported a concomitant worsening of muscle weakness and twelve patients (7.3%) suffered a cholinergic crisis. According to these patients, the severity of cholinergic side effects was greater at higher doses of AChEI, but side effects occurred regardless of the dose administered and ceased once the drug was discontinued. CONCLUSIONS: This is the largest population of MuSK-MG patients reported for perceived responsiveness and tolerance to AChEI treatment. Our obervations strongly suggest avoiding this treatment in MuSK-MG.

Medial tab-type fasciocutaneous flap as an alternative for the management of soft tissue defects of the leg. / Colgajo fasciocutáneo tipo lengüeta medial como alternativa para el manejo de defectos de tejidos blandos en la pierna.

BACKGROUND: Selecting the right technique for lower limb soft tissue reconstruction is a therapeutic challenge. Despite having several reconstruction options, it's important to choose a technique that is effective and with the least possible donor site morbidity. OBJECTIVE: Demonstrate the therapeutic efficacy of the medial tab flap in soft tissue reconstruction on the leg, compared to conventional flaps. MATERIALS AND METHODS: Cohort study matched by age. 64 patients with soft tissue defects were selected and according to the intervention divided in: group 1)medial tab flap, and group 2)conventional flaps (sural, soleus, gastrocnemius) followed up to one year postoperatively. OUTCOME VARIABLES: surgical time in minutes, healing, healing time in days, complications. RESULTS: The patients who underwent surgery with medial tab flap and with conventional flaps healed completely. The healing time was 16.2±11.2 days in the tab flap and 16.1±11.2 days in conventional flaps, no statistically significant differences were found between the groups (P=.89). The surgical time for tab flaps was 225.2±117.8minutes, and 191.3±117.2minutes for the comparison flaps (P=.65), there were no statistically significant differences. There were no complications in the medial tab flaps. CONCLUSION: The findings suggest that the medial tab flap technique is as effective as the conventional flap technique, with complete flap survival and healing, and without any major complications in this studied group.

Perceived misdiagnosis of psychiatric conditions in autistic adults.

Background: Many autistic people, particularly women, do not receive an autism diagnosis until adulthood, delaying their access to timely support and clinical care. One possible explanation is that autistic traits may initially be misinterpreted as symptoms of other psychiatric conditions, leading some individuals to experience misdiagnosis of other psychiatric conditions prior to their autism diagnosis. However, little is currently known about the frequency and nature of psychiatric misdiagnoses in autistic adults. Methods: Using data collected in the first half of 2019 from an ongoing longitudinal register of autistic adults in the Netherlands, this study explored the frequency of perceived psychiatric misdiagnoses before receiving an autism diagnosis. Gender differences were also explored. A sample of 1211 autistic adults (52.6% women, mean age 42.3 years), the majority of whom were Dutch and relatively highly educated, was evaluated. Findings: Results showed that 24.6% (n = 298) of participants reported at least one previous psychiatric diagnosis that was perceived as a misdiagnosis. Personality disorders were the most frequent perceived misdiagnoses, followed by anxiety disorders, mood disorders, chronic fatigue syndrome/burnout-related disorders, and attention-deficit/hyperactivity disorder. Autistic women (31.7%) reported perceived misdiagnoses more frequently than men (16.7%). Women were specifically more likely than men to report perceived misdiagnoses of personality disorders, anxiety disorders, and mood disorders. Women also reported prior psychiatric diagnoses more often in general (65.8% versus 34.2% in men). Within the group of individuals with a prior diagnosis, perceived misdiagnoses were equally likely for men and women. Interpretation: One in four autistic adults, and one in three autistic women, reported at least one psychiatric diagnosis, obtained prior to being diagnosed with autism, that was perceived as a misdiagnosis. Inaccurate diagnoses are linked to long diagnostic pathways and delayed recognition of autism. These findings highlight the need for improved training of mental health practitioners, in order to improve their awareness of the presentation of autism in adulthood and of the complex relationship between autism and co-occurring conditions. The current study constitutes a first step towards showing that autistic adults, and particularly women, may be at greater risk of experiencing misdiagnoses. Future studies based on larger, more representative samples are required, to replicate current findings and provide more reliable estimates of the overall frequency of misdiagnoses as well as the frequency of misdiagnoses for specific psychiatric conditions. Funding: This study was made possible by funding from the Netherlands Organisation for Health Research and Development (ZonMW), project number 60-63600-98-834.

Skin cancer risk behaviors in sexual minority men: A mixed methods approach.

OBJECTIVE: Sexual minority men experience disproportionately elevated rates of skin cancers, likely driven by excess ultraviolet radiation exposure-namely through tanning behaviors. However, limited integrated theoretical models exist to explain sexual minority men's elevated skin cancer risk. The aim of the current study is to further test and refine an integrated theory of skin cancer risk behaviors among sexual minority men by incorporating minority stress into the integrated health behavior model of tanning. METHOD: The study employed a parallel mixed methods design, with a Phase 1 qualitative stage (N = 30) and a Phase 2 quantitative stage (Model 1: N = 320; Model 2: N = 319). In both phases, participants were sexual minority men, equally stratified as those with versus without recent tanning exposure and were recruited from across the United States. RESULTS: Qualitative and quantitative data supported the overall integrated model, with some quantitative paths varying depending on the tanning behavior outcome. Overall, appearance-related motives to tan and beliefs that tanning regulates affect emerged as the most consistent proximal predictors. Minority stress significantly predicted holding more positive attitudes toward tanning as an effective affect regulation strategy. CONCLUSIONS: The results from this mixed methods study support the inclusion of minority stressors into the adapted integrative health behavior model of tanning. Replication within prospective designs would strengthen the evidence for this model, which may be helpful in guiding future skin cancer prevention programs tailored to sexual minority men. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages.

Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, in cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2-/- lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity.

Caregiver-centred empowerment for families raising autistic children: A qualitative case study from Argentina.

LAY ABSTRACT: Caregivers of children with developmental disabilities, including autism, often struggle to access services, information and resources in Argentina. Little is known about how caregivers can be empowered to support their children as they wish to in the Argentinian setting. We spoke with 32 people online to understand existing and potential practices of supporting caregivers. The people we spoke with included caregivers, health service providers, non-governmental organisations' representatives providing services or technical support, special education teachers and policy representatives. Participants said that poverty, and inequalities in accessing support, impact how caregivers can support their children. They mentioned examples that help caregivers feel empowered, such as peer support groups and caregiver training. Many caregivers spoke about how they became advocates for their children and how they developed initiatives such as advocacy campaigns and well-being support groups. Caregivers in Argentina may be empowered in various ways, and the following strategies can improve empowerment: strengthening collaboration between professionals and caregivers; focusing on caregiver mental health; and addressing the profound impact of poverty on the quality of life of families.

Choice of molecular marker influences spatial patterns of phylogenetic diversity.

Spatial patterns of phylogenetic diversity (PD) are increasingly becoming relevant for conservation decisions. PD measures are based on phylogenies estimated from molecular data. This paper addresses the question of how different molecular markers impact PD spatial patterns. We first conducted a simple simulation to explore the effect of deep and shallow changes in topology (simulating variations in molecular markers), using ultrametric and non-ultrametric trees, and then used a dataset of Chilean flora with four sets of markers to assess potential differences in spatial patterns of PD ranks using different markers and types of trees. The simulation consistently showed that the difference in PD rank was lower for ultrametric trees than for phylograms. A similar trend was observed using the Chilean flora dataset, with among-markers variability in spatial patterns of the PD metrics lower for ultrametric than for non-ultrametric trees, depicted as top 2.5 and 5% hotspots. Frequency distribution of PD values differed among markers as well, with this variation less apparent for ultrametric trees. We conclude that the choice of markers impacts spatial patterns of PD, and these results vary more strongly for phylograms, suggesting that ultrametric trees are more robust to the choice of marker.

The impact of raising a child with a developmental or physical health condition in Ethiopia.

OBJECTIVE: Raising a child with a developmental disability or physical health condition can have a major impact on the lives of their families, especially in low-income countries. We explored the impact on such families in Ethiopia. STUDY DESIGN: A total of 241 child-caregiver dyads were recruited from two public hospitals in Addis Ababa, Ethiopia. Of these, 139 children were diagnosed with a developmental disability (e.g. autism, intellectual disability) and 102 children with a physical health condition (e.g. malnutrition, severe HIV infection). The family quality of life was assessed using caregiver reports on the Pediatric Quality of Life Inventory™ (PedsQL-FIM™). The disability weight score, which is a Global Burden of Disease measure to quantify health loss, was estimated for each child. RESULTS: Families with a child with a developmental disability reported lower quality of life than families caring for a child with a physical health condition (p < .001). Mean disability weight scores in children with a developmental disability were higher than in children with a physical health condition (p < .001), indicating more severe health loss. Disability weight scores were negatively associated with the family quality of life in the whole group (B=-16.8, SE=7.5, p = .026), but not in the stratified analyses. CONCLUSIONS: Caring for a child with a developmental disability in Ethiopia is associated with a substantial reduction in the family quality of life. Scaling up support for these children in resource-limited contexts should be prioritized.

Borolatonin limits cognitive deficit and neuron loss while increasing proBDNF in ovariectomised rats.

BACKGROUND: Borolatonin is a potential therapeutic agent for some neuronal diseases such as Alzheimer's disease (AD). Its administration exerts ameliorative effects such as those induced by the equimolar administration of melatonin in behavioral tests on male rats and in neuronal immunohistochemistry assays. OBJECTIVE: In this study, motivated by sex differences in neurobiology and the incidence of AD, the ability of borolatonin to induce changes in female rats was assessed. METHODS: Effects of borolatonin were measured by the evaluation of both behavioral and immunohistopathologic approaches; additionally, its ability to limit amyloid toxicity was determined in vitro. RESULTS: Surprisingly, behavioral changes were similar to those reported in male rats, but not those evaluated by immunoassays regarding neuronal survival; while pro-brain-derived neurotrophic factor (BDNF) immunoreactivity and the limitation of toxicity by amyloid in vitro were observed for the first time. CONCLUSION: Borolatonin administration induced changes in female rats. Differences induced by the administration of borolatonin or melatonin could be related to the differences in the production of steroid hormones in sex dependence. Further studies are required to clarify the possible mechanism and origin of differences in disturbed memory caused by the gonadectomy procedure between male and female rats.

Factors Associated with Parametrial Involvement in Endometrial Carcinoma in Patients Treated with Radical Hysterectomy.

INTRODUCTION: Describe factors associated with parametrial involvement, and how these factors modify the prognosis of patients with endometrial carcinoma treated with radical hysterectomy. METHODS: Observational study in which categorized patients according to those with and without parametrial involvement. A descriptive analysis and comparative analysis were performed for associations between parametrial spread and clinical, surgical, and pathology variables. RESULTS: We analyzed 85 patients, which 18 (21%) had parametrial involvement. Pathology factors associated with parametrial involvement were the endometrioid subtype, grade 3, and variants of poor prognosis (odds ratio (OR) 3.41, 95% CI 1.09-10.64; P = 0.035), myometrial invasion of over 50% (OR 7.76, 95% CI 1.65-36.44; P = 0.009), serosal involvement (OR 17.07, 95% CI 3.87-75.35; P < 0.001), ovarian metastasis (OR 5.15, 95% CI 1.36-19.46; P = 0.016), positive peritoneal cytology (OR 3.9, 95% CI 1.04-14.77; P = 0.044), and lymph node metastasis (OR 3.4; 95% CI 1.16-9.97; P = 0.026). Five-year disease-free survival was 74% (95% CI 57.4-85.4) for the group without parametrial spread and 50.8% (95% CI 22.7-73.4) for the group with parametrial spread (P = 0.001). Similarly, 5-year overall survival was 85.2% (95% CI 67.9-93.6) for the group without parametrial spread and 47.5% (95% CI 8.1-80.2) for the group with parametrial spread (P = 0.002). CONCLUSION: Factors associated with parametrial involvement were histologies of poor prognosis, tumors affecting uterine serosa, cervix, or spread beyond the uterus. Additionally, parametrial involvement directly affects prognosis by reducing overall survival, disease-free survival and increasing odds for recurrence.