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Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7–22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6–33, P, Patients with solid cancers have high rates of clonal haematopoiesis associated with increased risk of secondary leukemias. Here, by using peripheral blood sequencing data from patients with solid non-hematologic cancer, the authors profile the landscape of mosaic chromosomal alterations and gene mutations, defining patients at high risk of leukemia progression.

Tissue plasminogen activator (tPA) is the only US Food and Drug Administration (FDA)–approved drug for ischemic stroke. However, delayed tPA administration is associated with increased risk of blood-brain barrier (BBB) disruption and hemorrhagic transformation (HT). Interferon-β (IFNβ), an FDA-approved drug for the treatment of multiple sclerosis, is a cytokine with immunomodulatory properties. Previous studies, including ours, demonstrated that IFNβ or type I IFN receptor signaling conferred protection against ischemic stroke in preclinical models, suggesting IFNβ might have translational therapeutic potential for the treatment of ischemic stroke. Currently, whether IFNβ could be coadministered with tPA to alleviate delayed tPA-induced adverse effects remains unknown. To elucidate that, IFNβ was coadministered with delayed tPA to ischemic stroke animals, and the severity and pathology of ischemic brain injury were assessed. We found delayed tPA treatment exacerbated ischemic brain injury, manifested by aggravated BBB disruption and HT. Notably, IFNβ ameliorated delayed tPA–exacerbated brain injury and alleviated adverse effects. Mechanistic studies revealed IFNβ suppressed tPA-enhanced neuroinflammation and MMP3/9 production in the ischemic brain. Furthermore, we identified IFNβ suppressed MMP9 production in microglia and attenuated tight junction protein degradation in brain endothelial cells. Moreover, we observed that peripheral immune cells may participate to a lesser extent in delayed tPA–exacerbated brain injury during the early phase of ischemic stroke. In conclusion, we provide the first evidence that IFNβ can be coadministered with tPA to mitigate delayed tPA–induced adverse effects of BBB disruption and HT that could potentially extend the tPA therapeutic window for the treatment of ischemic stroke.

Objectives. This study aims to study the epidemiological and geographic characteristics of the meningococcal serogroups four years after the introduction of serogroup A meningococcal conjugate vaccine. Methods. This is a prospective, descriptive, analytical study, and it took place from 2016 to 2018. Cerebrospinal fluid (CSF) samples were taken after the identification of meningitis cases. The samples, thus, taken were sent to the laboratory for culture and identification of Neisseria meningitidis in accordance with WHO standards. Results. Eight hundred and ninety-nine bacterial strains were identified, of which 219 were strains of Neisseria meningitidis. The majority of N. meningitidis-positive samples were from male patients (59.8%) with a median age of 4 (IQR: 1–13). Four of N. meningitidis serogroups were identified, namely, serogroups C (6.8%), W (19.6%), X (1.8%), and A (0.5%). Geographically, 92.7% of the identified N. meningitidis serogroups came from patients who lived in the northern region of the country. The departments most concerned were Alibori (N. meningitidis C (66.7%) and N. meningitidis W (20.9%)); Atacora (N. meningitidis W (41.9%), N. meningitidis X (75.0%), and N. meningitidis C (13.3%)); and Borgou (N. meningitidis W (23.3%)). Conclusion. The results of this study showed that there is an emergence of cases of meningococcal of serogroup C four years after the introduction of MenAfricVac in Benin. These results demonstrated the effectiveness of case-by-case surveillance in detecting small changes in the distribution of serogroups that could have important implications for public health strategies in the coming seasons.

Pervasive refusal syndrome (PRS) is a complex condition that affects young people leading to social withdrawal, inability or refusal to eat, drink, mobilise or speak. The affected individual regresses and is unable to self-care and quite characteristically will resist rehabilitation, worsen with praise or remain entirely passive. This systematic review was aimed at describing clinical features of PRS, current interventions and to summarise some of the nosological aspects of the condition. Without language restriction, an electronic search was conducted in Embase, PsychInfo, Medline, Cochrane library, and PubMed databases yielding 29 articles with a total of 79 cases. We performed a risk of assessment bias using an adapted Newcastle–Ottawa Scale and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 124 articles were identified, of which 29 were included and these yielded 79 cases. Seventy-six percent of the studies had a low rate of risk of assessment bias (good quality). Our results show that PRS overlaps with several conditions, mainly affects young females aged 7–15 years and has a recovery rate of 78% if diagnosed and treated early but the duration of inpatient treatment may last up to 9.44 months (8.82 SD). The patients had multiple inter-dependent risks. The major predisposing factors included vulnerable premorbid personality and pre-existing mental disorder. Precipitating factors were stressors such as infection and traumatic experiences. Enmeshed parent–child relationship served as a maintaining factor. The themes of treatment approach are essentially rehabilitative: (1) working collaboratively with patient and family, (2) having access to multidisciplinary team, and (3) peer/group supervision. This study has systematically evaluated a large sample of patients with PRS to ascertain its clinical features and the core elements of its treatment. Its key treatment approach is a multi-modal rehabilitative strategy that is compassionate, transparent and inclusive. Electronic supplementary material The online version of this article (10.1007/s00787-020-01536-1) contains supplementary material, which is available to authorized users.

Background: Bacterial meningitis is an inflammation of the meninges caused mainly by three bacterial species Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae that are transmitted by nasopharyngeal secretions emitted by carriers. Meningitis is a public health problem in Benin, like all countries in the African meningitis belt. This study aims to analyze the epidemiological surveillance data of meningitis in Benin from 2016 to 2018. Methods: Each suspect case of meningitis was recorded and Cerebrospinal Fluid (CSF) samples were collected. CSF collection was accompanied by the Integrated Disease Surveillance and Response form. This sheet provides information on the patient’s social-demographic and epidemiological data. CSF specimens were sent to the laboratory for analysis and identification (Gram stain, biochemical parameters, and latex agglutination test) of pathogens according to the WHO standards. Results: Of the 2992 patients with suspected meningitis, 2893 were hospitalized with a death rate of 9.4% (281/2992). The sex ratio of registered patients was 1.29 in favor of men. The median age was 4 years (min: 0; max: 90). Patients younger than five years were the most represented (44.8%). During the study period, there was a decrease in the incidence of meningitis per 100,000 inhabitants (6.3 to 3.2 from 2016 to 2018). Of 2928 CSF samples collected we were able to identify 899 pathogenic bacterial species. The most represented species are S. pneumoniae (63.4%), N. meningitidis (24.4%) and H. influenzae (12.2%). Conclusion: The burden of disease is disproportionate in the northern departments as in others. The frequency of bacterial meningitis in the northern region increased during the study period. However, deaths have been recorded in the departments of the South (“Atlantic”, “Plateau”). This suggests an improvement in epidemiological surveillance and case management throughout the national territory.

Cancer cells display two modes of focal amplifications (FAs), extrachromosomal DNA/double-minutes (ecDNA/DMs) and intrachromosomal homogenously staining regions (HSRs). Understanding the plasticity of these two modes is critical for preventing targeted therapy resistance. We developed a combined BRAF plus MEK inhibitor resistance melanoma model that bears high BRAF amplifications through both DM and HSR modes, and investigated FA dynamics in the context of drug resistance plasticity. Cells harboring FAs displayed mode switching between DMs and HSRs, from both de novo genetic changes and selection of preexisting subpopulations. We found that copy number plasticity is not exclusive to DMs. Single cell-derived clones with HSRs also exhibit BRAF copy number and corresponding HSR length plasticity that allows them to respond to dose reduction and recover from drug addiction. Upon kinase inhibitor escalation, we observed reproducible selection for cells with BRAF kinase domain duplications residing on DMs. In sum, the plasticity of FAs allows cancer cells to respond to drug dose changes through a myriad of mechanisms. These mechanisms include increases or decreases in DMs, shortening of HSRs, acquisition of secondary resistance mechanisms, and expression of alternative slicing oncogene variants. These results highlight the challenges in targeting the cellular vulnerabilities tied to focal amplifications.Statement of SignificanceUnderstanding the dynamics of oncogene amplifications is critical for appreciating tumorigenesis and preventing anticancer drug resistance. We found melanoma cells harboring BRAF amplifications in either DM or HSR formats to have high plasticity under different kinase inhibitor dosage challenges with evidence supporting de novo alterations, clonal selection, and coupling to additional resistance mechanisms. In in the absence of DMs, HSRs can offer comparable levels of plasticity as DMs.

Introduction: New treatments have been introduced with the objective to increase the survival rate of oncologic patients. As a result of these approaches, there was an increase in the number of cases of toxicity and complications, which can lead to acute respiratory failure (ARF). One of the most frequent ways to treat ARF is non-invasive ventilation (NIV). Despite the proven benefits in several clinical conditions, NIV results in cancer patients are controversial. Objective: To evaluate risk factors associated with NIV failure and hospital mortality in oncologic patients. Methods: Retrospective cohort study including patients with solid tumors and hematological neoplasms admitted for hospitalization at National Cancer Institute between January 1, 2017 and December 31, 2019, who underwent NIV. The association between the variables of exposure and the outcome was performed by gross and adjusted logistic regression. The Kaplan-Meier method was used to analyze the length of hospital stay. Results: Sixty-three patients who underwent NIV in hospitalization were evaluated, and 26 failed NIV. The patients had a mean age of 58.5 years (±15.6), most were male (57.1%), under 60 years old (58.7%) and had comorbidities (55.5%). The patients with pulmonary infection (OR 6.53; 95% CI 1.21-35.12; p=0.02) had a higher risk of failure in NIV. In relation to hospital mortality, patients older than 60 years (OR 6.90; 95% CI, 2.12-22.45; p=0.001) had a higher risk. Conclusion: Patients who presented pulmonary infection were more likely to fail in NIV. Higher hospital mortality was observed among elderly patients. Introducción: Se han introducido nuevos tratamientos con el objetivo de aumentar la supervivencia de los pacientes con cáncer. Por tanto, aumenta el número de casos de complicaciones y toxidades que pueden derivar en insuficiencia respiratoria aguda (IRA). Una de las formas más frecuentes de tratar la IRA es la ventilación no invasiva (VNI). A pesar de los beneficios em varias condiciones clínicas, el uso de VNI em pacientes con cáncer es controvertido. Objetivo: Evaluar los factores asociados con el fracaso de la VNI y la mortalidad. Métodos: Estudio retrospectivo que incluye pacientes con tumores sólidos y neoplasias hematológias ingresados para hospitalización em el Instituto Nacional del Cáncer entre el 1 de enero de 2017 y el 31 de diciembre de 2019 y que se sometieron a VNI. La asociación entre la exposición y las variables de resultado se realizó mediante regresión logística. Se utilizo el método de Kaplan-Meier para analizar la duración de la estancia hospitalaria. Resultados: Se evaluaron 63 pacientes que fueron sometidos a VNI durante la hospitalización y 26 tuvieron falla de VNI. La edad media fue de 58,5 años (±15.6), la mayoría eran hombres (57,1%), menores de 60 años y tenían comorbilidades (55,5%). Los pacientes con infección pulmonar (OR 6,53; IC 95% 1,21-35,12; p=0,02) tenían un mayor riesgo de fracaso de la VNI y, en relación con la mortalidad hospitalaria, los pacientes mayores de 60 años (OR 6,90; IC 95%, 2,12-22,45; p=0,001) tenían un mayor riesgo de muerte. Conclusión: Los pacientes con infección pulmonar tenían más probabilidades de fracasar en la VNI y se observó una mayor mortalidad entre los ancianos. Introdução: Novos tratamentos têm sido introduzidos visando o aumento da sobrevida dos pacientes oncológicos. Com isso, existe um aumento do número de casos de complicações e toxidades que podem levar a insuficiência respiratória aguda (IRA). Um dos caminhos mais frequente para tratamento da IRA é a ventilação não invasiva (VNI). Apesar dos benefícios em diversas condições clínicas, o uso da VNI em pacientes oncológicos é controverso. Objetivo: Avaliar os fatores associados a falha da VNI e a mortalidade hospitalar em pacientes oncológicos. Métodos: Trata-se de um estudo de coorte retrospectivo incluindo pacientes com tumores sólidos e neoplasias hematológicas admitidos para internação hospitalar no Instituto Nacional de Câncer entre 1 de Janeiro de 2017 e 31 de dezembro de 2019 e que realizaram VNI. A associação entre as variáveis de exposição e de desfecho foram realizadas através da regressão logística. O método de Kaplan-Meier foi usado para análise do tempo de internação hospitalar. Resultados: Sessenta e três pacientes que realizaram VNI durante a internação foram avaliados e 26 apresentaram falha na VNI. A média de idade era de 58,5 anos (±15.6), a maioria eram homens (57,1%), menos de 60 anos (58,7%) e tinha comorbidades (55,5%). Os pacientes com infecção pulmonar (OR 6,53; IC 95% 1,21-35,12; p=0,02) tinham maior risco de falha na VNI e em relação a mortalidade hospitalar, pacientes com mais de 60 anos (OR 6,90; IC 95%, 2,12-22,45; p=0,001) tinham maior risco de morte. Conclusão: Pacientes com infecção pulmonar tinham mais chance de falhar na VNI e uma maior mortalidade foi observada entre os idosos.

BackgroundCOVID-19 is a multi-system disease and patients who survive may experience in-hospital complications. These complications are likely to have important short and long-term consequences for patients, healthcare utilisation, healthcare system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and impact of COVID-19 complications, particularly in those who survive using the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK).MethodsA multicentre, prospective cohort study in 302 UK healthcare facilities of adults hospitalised with COVID-19 between 17th January and 4th August 2020. Complications were defined as organ specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. Outcomes included death, critical care use, and ability to self-care at hospital discharge. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities.ResultsOf patients admitted to hospital for management of COVID-19, 49.7% (36 367/73 197) experienced at least one complication. The mean age of our cohort was 71.1 years old (SD 18.7), included more males (56.0%, 41 025/73 ) with 81.0% (59 289/73 197) of patients having at least one comorbidity. Males over 60 were most likely to experience a complication (60 y and over, 54.5% [16 579/30 416] in males and 48.2% [11 707/24 288] in females; Under 60 y, 48.8% [5179/10 609] in males, 36.6% [2814/7689] in females). Renal (24.3%, 17 752/73 197), complex respiratory 18.4% (13 486/73 197), and systemic (16.3%, 11 895/73 197) complications were most frequent. Cardiovascular (12.3%, 8973/73 197), neurological (4.3%, 3115/73 197), and gastrointestinal/liver (0.8%, 7901/73 197) complications were also reported. The presence of any complication was associated with significantly worse survival (adjusted HR 1.74, 95% CI 1.64 to 1.84) and increased admission to critical care (adjusted OR 7.25, 95% CI 6.83 to 7.69). Reduced ability to self-care at discharge was significantly greater in patients who experienced a complication (adjusted OR 2.42, 95% CI 2.31 to 2.54) and was greatest in those who experienced neurological complications (adjusted OR 4.39, 95% CI 3.95 to 4.89). ConclusionsComplications and worse functional outcomes in patients admitted to hospital with COVID-19 are high, even in young, previously healthy individuals. Acute complications are associated with reduced ability to self-care at discharge, with neurological complications being associated with the worst functional outcomes. COVID-19 complications are likely to cause significant strain on health and social care in the coming years. These data will help in the design and provision of services aimed at the post-hospitalisation care of patients with COVID-19.

Objective: the aim of this study was to investigate the association of obesity with in-hospital coronavirus disease 2019 (COVID-19) outcomes in different ethnic groups.Methods: patients admitted to hospital with COVID-19 in the United Kingdom through the Clinical Characterisation Protocol UK (CCP-UK) developed by the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) were included from February 6 to October 12, 2020. Ethnicity was classified as White, South Asian, Black, and other minority ethnic groups. Outcomes were admission to critical care, mechanical ventilation, and in-hospital mortality, adjusted for age, sex, and chronic diseases.Results: of the participants included, 54,254 (age = 76 years; 45.0% women) were White, 3,728 (57 years; 41.1% women) were South Asian, 2,523 (58 years; 44.9% women) were Black, and 5,427 (61 years; 40.8% women) were other ethnicities. Obesity was associated with all outcomes in all ethnic groups, with associations strongest for black ethnicities. When stratified by ethnicity and obesity status, the odds ratios for admission to critical care, mechanical ventilation, and mortality in black ethnicities with obesity were 3.91 (3.13-4.88), 5.03 (3.94-6.63), and 1.93 (1.49-2.51), respectively, compared with White ethnicities without obesity.Conclusions: obesity was associated with an elevated risk of in-hospital COVID-19 outcomes in all ethnic groups, with associations strongest in Black ethnicities.

BACKGROUND: Studies of patients admitted to hospital with COVID-19 have found varying mortality outcomes associated with underlying respiratory conditions and inhaled corticosteroid use. Using data from a national, multicentre, prospective cohort, we aimed to characterise people with COVID-19 admitted to hospital with underlying respiratory disease, assess the level of care received, measure in-hospital mortality, and examine the effect of inhaled corticosteroid use. METHODS: We analysed data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study. All patients admitted to hospital with COVID-19 across England, Scotland, and Wales between Jan 17 and Aug 3, 2020, were eligible for inclusion in this analysis. Patients with asthma, chronic pulmonary disease, or both, were identified and stratified by age ( FINDINGS: 75 463 patients from 258 participating health-care facilities were included in this analysis: 860 patients younger than 16 years (74 [8·6%] with asthma), 8950 patients aged 16-49 years (1867 [20·9%] with asthma), and 65 653 patients aged 50 years and older (5918 [9·0%] with asthma, 10 266 [15·6%] with chronic pulmonary disease, and 2071 [3·2%] with both asthma and chronic pulmonary disease). Patients with asthma were significantly more likely than those without asthma to receive critical care (patients aged 16-49 years: adjusted odds ratio [OR] 1·20 [95% CI 1·05-1·37]; p=0·0080; patients aged ≥50 years: adjusted OR 1·17 [1·08-1·27]; p INTERPRETATION: Underlying respiratory conditions are common in patients admitted to hospital with COVID-19. Regardless of the severity of symptoms at admission and comorbidities, patients with asthma were more likely, and those with chronic pulmonary disease less likely, to receive critical care than patients without an underlying respiratory condition. In patients aged 16 years and older, severe asthma was associated with increased mortality compared to non-severe asthma. In patients aged 50 years and older, inhaled corticosteroid use in those with asthma was associated with lower mortality than in patients without an underlying respiratory condition; patients with chronic pulmonary disease had significantly increased mortality compared to those with no underlying respiratory condition, regardless of inhaled corticosteroid use. Our results suggest that the use of inhaled corticosteroids, within 2 weeks of admission, improves survival for patients aged 50 years and older with asthma, but not for those with chronic pulmonary disease. FUNDING: National Institute for Health Research, Medical Research Council, NIHR Health Protection Research Units in Emerging and Zoonotic Infections at the University of Liverpool and in Respiratory Infections at Imperial College London in partnership with Public Health England.

Background Early in the pandemic it was suggested that pre-existing use of non-steroidal anti-inflammatory drugs (NSAIDs) could lead to increased disease severity in patients with COVID-19. NSAIDs are an important analgesic, particularly in those with rheumatological disease, and are widely available to the general public without prescription. Evidence from community studies, administrative data, and small studies of hospitalised patients suggest NSAIDs are not associated with poorer COVID-19 outcomes. We aimed to characterise the safety of NSAIDs and identify whether pre-existing NSAID use was associated with increased severity of COVID-19 disease. Methods This prospective, multicentre cohort study included patients of any age admitted to hospital with a confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 between Jan 17 and Aug 10, 2020. The primary outcome was in-hospital mortality, and secondary outcomes were disease severity at presentation, admission to critical care, receipt of invasive ventilation, receipt of non-invasive ventilation, use of supplementary oxygen, and acute kidney injury. NSAID use was required to be within the 2 weeks before hospital admission. We used logistic regression to estimate the effects of NSAIDs and adjust for confounding variables. We used propensity score matching to further estimate effects of NSAIDS while accounting for covariate differences in populations. Results Between Jan 17 and Aug 10, 2020, we enrolled 78 674 patients across 255 health-care facilities in England, Scotland, and Wales. 72 179 patients had death outcomes available for matching; 40 406 (56·2%) of 71 915 were men, 31 509 (43·8%) were women. In this cohort, 4211 (5·8%) patients were recorded as taking systemic NSAIDs before admission to hospital. Following propensity score matching, balanced groups of NSAIDs users and NSAIDs non-users were obtained (4205 patients in each group). At hospital admission, we observed no significant differences in severity between exposure groups. After adjusting for explanatory variables, NSAID use was not associated with worse in-hospital mortality (matched OR 0·95, 95% CI 0·84–1·07; p=0·35), critical care admission (1·01, 0·87–1·17; p=0·89), requirement for invasive ventilation (0·96, 0·80–1·17; p=0·69), requirement for non-invasive ventilation (1·12, 0·96–1·32; p=0·14), requirement for oxygen (1·00, 0·89–1·12; p=0·97), or occurrence of acute kidney injury (1·08, 0·92–1·26; p=0·33). Interpretation NSAID use is not associated with higher mortality or increased severity of COVID-19. Policy makers should consider reviewing issued advice around NSAID prescribing and COVID-19 severity. Funding National Institute for Health Research and Medical Research Council.

Objective The aim of the study was to compare 6-month efficacy and safety for treatment of vaginal dryness/genitourinary syndrome of menopause in women undergoing fractionated CO2 vaginal laser therapy to women using estrogen vaginal cream. Methods This multicenter, randomized trial compared fractionated CO2 laser to estrogen cream at 6 institutions. We included menopausal women with significant vaginal atrophy symptoms and we excluded women with prolapse below stage 2, recent pelvic surgery, prior mesh surgery, active genital infection, history of estrogen sensitive malignancy, and other autoimmune conditions. The primary outcome was the visual analog scale vaginal dryness score. Secondary outcomes included evaluation of vaginal atrophy, quality of life symptoms, assessment of sexual function, and urinary symptoms. Adverse events (AEs) and patient global impression of improvement (PGI-I) and satisfaction were also assessed. Results Sixty-nine women were enrolled in this trial before enrollment was closed due to the Federal Drug Administration requiring the sponsor to obtain and maintain an Investigational Device Exemption. Of the 69 participants enrolled, 62 completed the 6-month protocol; 30 women were randomized to the laser and 32 to estrogen cream from June 2016 to September 2017. Demographics did not differ between groups except the laser group was less parous (0 [range 0-4] vs 2 [0-6], P = 0.04). On patient global impression, 85.8% of laser participants rated their improvement as "better or much better" and 78.5% reported being either "satisfied or very satisfied" compared to 70% and 73.3% in the estrogen group; this was not statistically different between groups. On linear regression, mean difference in female sexual function index scores was no longer statistically significant; and, vaginal maturation index scores remained higher in the estrogen group (adj P value 0.02); although, baseline and 6-month follow-up vaginal maturation index data were only available for 34 participants (16 laser, 18 estrogen). Conclusions At 6 months, fractionated CO2 vaginal laser and vaginal estrogen treatment resulted in similar improvement in genitourinary syndrome of menopause symptoms as well as urinary and sexual function. Overall, 70% to 80% of participants were satisfied or very satisfied with either treatment and there were no serious adverse events. : Video Summary:http://links.lww.com/MENO/A470.

Pre-operative assessments, which include patient history and physical examination, are fundamental in ensuring patient education about their procedure, and leads to successful post-operative outcomes. Within Niagara Health (NH), there are three main hospital sites where operations occur. Currently, there is inconsistency in the pre-operative assessments between sites for the same surgical procedures, demonstrated by variation in pre-operative assessment times, activities, and information given to patients. The aim of this project is to understand where standardization through quality improvement (QI) initiatives should begin within these pre-operative assessment clinics and determine the feasibility of standardization across varying hospital sites. To achieve this aim, Plan, Do, Study, Act (PDSA) cycles were conducted and involved structured observations at each site to gain a comprehensive understanding of pre-operative practices across sites. Root cause analysis found moderate correlation at two sites and strong correlation at one site between patient age and consult time. Affinity analysis determined that the most pragmatic and feasible area for improvement was through standardization of admission history forms. While the piloting of a new standardized form showed no significant increase in consult times, fundamental barriers such as nursing staff turnover, lack of familiarity with the new form, and concerns of comprehensiveness prevented the continuation of this new standardized form. Future attempts at standardization should begin with collaboration and co-design with pre-op clinic staff, followed by identification of elements of the complex adaptive system that can feasibly be standardized to reduce unnecessary variation while at the same time increasing buy-in for form use.

The farnesoid X receptor (FXR) plays a critical role in the regulation of lipid and bile acid (BA) homeostasis. Hepatic FXR loss results in lipid and BA accumulation, and progression from hepatic steatosis to nonalcoholic steatohepatitis (NASH). This study aimed to evaluate the effects of xanthohumol (XN), a hop-derived compound mitigating metabolic syndrome, on liver damage induced by diet and FXR deficiency in mice. Wild-type (WT) and liver-specific FXR-null mice (FXRLiver−/−) were fed a high-fat diet (HFD) containing XN or the vehicle formation followed by histological characterization, lipid, BA and gene profiling. HFD supplemented with XN resulted in amelioration of hepatic steatosis and decreased BA concentrations in FXRLiver−/− mice, the effect being stronger in male mice. XN induced the constitutive androstane receptor (CAR), pregnane X receptor (PXR) and glucocorticoid receptor (GR) gene expression in the liver of FXRLiver−/− mice. These findings suggest that activation of BA detoxification pathways represents the predominant mechanism for controlling hydrophobic BA concentrations in FXRLiver−/− mice. Collectively, these data indicated sex-dependent relationship between FXR, lipids and BAs, and suggest that XN ameliorates HFD-induced liver dysfunction via FXR-dependent and independent signaling.

Background Vaginal hysterectomy with suture apical suspension is commonly performed for uterovaginal prolapse. Sacrospinous hysteropexy with graft (vaginal mesh hysteropexy) is an alternative, although in 2019 the Food and Drug Administration removed this mesh product from the United States market. Objective Our objective was to compare the efficacy and adverse events of these 2 procedures. Study Design At 9 clinical sites in the United States National Institutes of Health and National Institute of Child Health and Human Development Pelvic Floor Disorders Network, 183 postmenopausal women requesting vaginal surgery for symptomatic uterovaginal prolapse were enrolled in a multisite randomized superiority clinical trial, comparing a sacrospinous hysteropexy with graft (hysteropexy) with a vaginal hysterectomy with uterosacral ligament suspension (hysterectomy). Participants consented to remain masked to treatment assignment for the study duration. Study visits were conducted at 6-month intervals through 60 months. The primary treatment failure composite outcome (retreatment of prolapse, prolapse beyond the hymen, or prolapse symptoms) was evaluated with survival modeling. Secondary outcomes included complications or adverse events, individual anatomic measures of the pelvic organ prolapse quantification examination, and presence, severity, and impact and bother of prolapse, urinary, bowel, and pain symptoms as measured by validated questionnaires. The 3-year published results suggested better primary outcomes with sacrospinous hysteropexy with graft, but the differences were not statistically significant (P=.06). This study reports the 5-year outcomes. Results A total of 183 women with a mean age of 66 years were randomized between April 2013 and February 2015; 93 were randomized to hysteropexy and 90 were randomized to hysterectomy. Notably, 175 were included in the trial, and 156 (89%) completed the 5-year follow-up. The primary outcome showed fewer failures for hysteropexy than hysterectomy through 5 years (adjusted hazard ratio, 0.58; 95% confidence interval, 0.36–0.94; P=.03), with failure rates of 37% vs 54%, respectively, resulting in a difference of −18% (95% confidence interval, −33% to −3%) at 5 years. With the exception of the Urogenital Distress Inventory, no group differences were demonstrated in patient-reported pelvic floor symptoms, prolapse symptoms, bowel function symptoms, general quality of life, body image, or pelvic pain. At their last visit through 5 years, 70% of participants (129 of 183) reported they remained masked to their treatment with no difference in masking between groups. Adverse events for hysteropexy vs hysterectomy included mesh exposure (8% vs 0%), granulation tissue after 12 weeks (1% vs 12%), and suture exposure after 12 weeks (3% vs 21%), respectively. Conclusion Among women with symptomatic uterovaginal prolapse undergoing vaginal surgery, sacrospinous hysteropexy with graft resulted in a lower composite failure rate than vaginal hysterectomy through 5 years. There were no meaningful differences in patient-reported outcomes between groups. Our results suggest that this vaginal mesh hysteropexy procedure should be made available to patients.

Inflammatory stimuli induce immunoresponsive gene 1 expression that in turn catalyses the production of itaconate through diverting cis-aconitate away from the tricarboxylic acid cycle. The immunoregulatory effect of the immunoresponsive gene 1/itaconate axis has been recently documented in lipopolysaccharide-activated mouse and human macrophages. In addition, dimethyl itaconate, an itaconate derivative, was reported to ameliorate disease severity in the animal models of psoriasis and multiple sclerosis. Currently, whether immunoresponsive gene 1/itaconate axis exerts a modulatory effect in ischaemic stroke remains unexplored. In this study, we investigated whether immunoresponsive gene 1 plays a role in modulating ischaemic brain injury. In addition, the molecular mechanism underlying the protective effects of immunoresponsive gene 1 in ischaemic stroke was elucidated. Our results showed that immunoresponsive gene 1 was highly induced in the ischaemic brain following ischaemic injury. Interestingly, we found that IRG1−/− stroke animals exhibited exacerbated brain injury, displayed with enlarged cerebral infarct, compared to wild-type stroke controls. Furthermore, IRG1−/− stroke animals presented aggravated blood–brain barrier disruption, associated with augmented Evans blue leakage and increased immune cell infiltrates in the ischaemic brain. Moreover, IRG1−/− stroke animals displayed elevated microglia activation, demonstrated with increased CD68, CD86 and Iba1 expression. Further analysis revealed that immunoresponsive gene 1 was induced in microglia after ischaemic stroke, and deficiency in immunoresponsive gene 1 resulted in repressed microglial heme oxygenase-1 expression and exacerbated ischaemic brain injury. Notably, the administration of dimethyl itaconate to compensate for the deficiency of immunoresponsive gene 1/itaconate axis led to enhanced microglial heme oxygenase-1 expression, alleviated ischaemic brain injury, improved motor function and decreased mortality in IRG1−/− stroke animals. In summary, we demonstrate for the first time that the induction of immunoresponsive gene 1 in microglia following ischaemic stroke serves as an endogenous protective mechanism to restrain brain injury through heme oxygenase-1 up-regulation. Thus, our findings suggest that targeting immunoresponsive gene 1 may represent a novel therapeutic approach for the treatment of ischaemic stroke., Kuo et al. reported that the induction of immunoresponsive gene 1 may serve as an endogenous protective mechanism to restrain brain injury following ischaemic stroke. Thus, their study suggests that targeting immunoresponsive gene 1 may represent a novel therapeutic approach for the treatment of ischaemic stroke., Graphical Abstract Graphical Abstract

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established. Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population. Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non–idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death. Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17–2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Background Multiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, axonal injury, and neuronal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model that mimics the key features of MS. Presently, the dietary consumption of foods rich in phenols has been reported to offer numerous health benefits, including anti-inflammatory activity. One such compound, 4-ethylguaiacol (4-EG), found in various foods, is known to attenuate inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unknown. Thus, in this study, we assessed the therapeutic effect of 4-EG in EAE using both chronic and relapsing-remitting animal models and investigated the immunomodulatory effects of 4-EG on neuroinflammation and Th1/Th17 differentiation in EAE. Methods Chronic C57BL/6 EAE and relapsing-remitting SJL/J EAE were induced followed by 4-EG treatment. The effects of 4-EG on disease progression, peripheral Th1/Th17 differentiation, CNS Th1/Th17 infiltration, microglia (MG) activation, and blood-brain barrier (BBB) disruption in EAE were evaluated. In addition, the expression of MMP9, MMP3, HO-1, and Nrf2 was assessed in the CNS of C57BL/6 EAE mice. Results Our results showed that 4-EG not only ameliorated disease severity in C57BL/6 chronic EAE but also mitigated disease progression in SJL/J relapsing-remitting EAE. Further investigations of the cellular and molecular mechanisms revealed that 4-EG suppressed MG activation, mitigated BBB disruption, repressed MMP3/MMP9 production, and inhibited Th1 and Th17 infiltration in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE and in vitro Th1 and Th17 cultures. Finally, we found 4-EG induced HO-1 expression in the CNS of EAE in vivo as well as in MG, BV2 cells, and macrophages in vitro. Conclusions Our work demonstrates that 4-EG confers protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1 and Th17 differentiation, suggesting 4-EG, a natural compound, could be potentially developed as a therapeutic agent for the treatment of MS/EAE.

Scope Sphingolipids including ceramides are implicated in the pathogenesis of obesity and insulin resistance. Correspondingly, inhibition of pro-inflammatory and neurotoxic ceramide accumulation prevents obesity-mediated insulin resistance and cognitive impairment. Increasing evidence suggests the farnesoid X receptor (FXR) is involved in ceramide metabolism, as bile acid-FXR crosstalk controls ceramide levels along the gut-liver axis. The authors previously reported that FXR agonist xanthohumol (XN), the principal prenylated flavonoid in hops (Humulus lupulus), and its hydrogenated derivatives, α,β-dihydroxanthohumol (DXN), and tetrahydroxanthohumol (TXN), ameliorated obesity-mediated insulin resistance, and cognitive impairment in mice fed a high-fat diet. Methods and results To better understand how the flavonoids improve both, lipid and bile acid profiles in the liver are analyzed, sphingolipid relative abundance in the hippocampus is measured, and linked them to metabolic and neurocognitive performance. XN, DXN, and TXN (30 mg kg-1 BW per day) decrease ceramide content in liver and hippocampus; the latter is linked to improvements in spatial learning and memory. In addition, XN, DXN, and TXN decrease hepatic cholesterol content by enhancing de novo synthesis of bile acids. Conclusion These observations suggest that XN, DXN, and TXN may alleviate obesity-induced metabolic and neurocognitive impairments by targeting the liver-brain axis.

Background Inflammatory stimuli induce immunoresponsive gene 1 (IRG1) expression that in turn catalyzes the production of itaconate from the tricarboxylic acid cycle. Itaconate has recently emerged as a regulator of immune cell functions, especially in macrophages. Studies show that itaconate is required for the activation of anti-inflammatory transcription factor Nrf2 by LPS in mouse and human macrophages, and LPS-activated IRG1-/- macrophages that lack endogenous itaconate production exhibit augmented inflammatory responses. Moreover, dimethyl itaconate (DMI), an itaconate derivative, inhibits IL-17-induced IκBς activation in keratinocytes and modulates IL-17-IκBς pathway-mediated skin inflammation in an animal model of psoriasis. Currently, the effect of itaconate on regulating macrophage functions and peripheral inflammatory immune responses is well established. However, its effect on microglia (MG) and CNS inflammatory immune responses remains unexplored. Thus, we investigated whether itaconate possesses an immunomodulatory effect on regulating MG activation and CNS inflammation in animal models of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Methods Chronic C57BL/6 EAE was induced followed by DMI treatment. The effect of DMI on disease severity, blood-brain barrier (BBB) disruption, MG activation, peripheral Th1/Th17 differentiation, and the CNS infiltration of Th1/Th17 cells in EAE was determined. Primary MG was cultured to study the effect of DMI on MG activation. Relapsing-remitting SJL/J EAE was induced to assess the therapeutic effect of DMI. Results Our results show DMI ameliorated disease severity in the chronic C57BL/6 EAE model. Further analysis of the cellular and molecular mechanisms revealed that DMI mitigated BBB disruption, inhibited MMP3/MMP9 production, suppressed microglia activation, inhibited peripheral Th1/Th17 differentiation, and repressed the CNS infiltration of Th1 and Th17 cells. Strikingly, DMI also exhibited a therapeutic effect on alleviating severity of relapse in the relapsing-remitting SJL/J EAE model. Conclusions We demonstrate that DMI suppresses neuroinflammation and ameliorates disease severity in EAE through multiple cellular and molecular mechanisms, suggesting that DMI can be developed as a novel therapeutic agent for the treatment of MS/EAE through its immunomodulatory and anti-inflammatory properties.

The crucial balance of stability in blood-circulation and tumor-specific delivery has been suggested as one of the challenges for effective bench-to-bedside translation of nanomedicines (NMs). Herein, we developed a supramolecularly enabled tumor-extracellular (Tex) pH-triggered NM that can maintain the micellar structure with the entrapped-drug during systemic circulation and progressively release drug in the tumor by rightly sensing heterogeneous tumor-pH. Desacetylvinblastine hydrazide (DAVBNH), a derivative of potent anticancer drug vinblastine, was conjugated to an aliphatic ketone-functionalized poly(ethylene glycol)-b-poly(amino acid) copolymer and the hydrolytic stability of the derived hydrazone bond was efficiently tailored by exploiting the compartmentalized structure of polymer micelle. We confirmed an effective and safe therapeutic application of Tex pH-sensitive DAVBNH-loaded micelle (Tex-micelle) in orthotopic glioblastoma (GBM) models, extending median survival to 1.4 times in GBM xenograft and 2.6 times in GBM syngeneic model, compared to that of the free DAVBNH. The work presented here offers novel chemical insights into the molecular design of smart NMs correctly sensing Tex-pH via programmed functionalities. The practical engineering strategy based on a clinically relevant NM platform, and the encouraging therapeutic application of Tex-micelle in GBM, one of the most lethal human cancers, thus suggests the potential clinical translation of this system against other types of common cancers, including GBM.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies. Environmental exposures shape patterns of selection for mutations in clonal hematopoiesis. Cancer therapies promote the growth of clones with mutations that are strongly enriched in treatment-related myeloid neoplasms.

Osteonecrosis occurs by cellular death of the bone tissue due to an irreversible external factor. This disorder may be clinically unidentified in the early stages and result in degradation of the bone architectural structure, leading to pain, bone destruction, and loss of function. Thus, imaging exams become relevant to the recognition and definition of the bone necroses. The aim of this study was to review the literature on imaging exams frequently used for the diagnosis and evaluation of patients undergoing drug therapies associated with osteonecrosis of the jaw, such as panoramic radiography, computed tomography, magnetic resonance imaging and bone scintigraphy.

Rationale: Although proposed as a clinical prompt to sepsis based on predictive validity for mortality, the Quick Sepsis-related Organ Failure Assessment (qSOFA) score is often used as a screening tool, which requires high sensitivity.Objectives: To assess the predictive accuracy of qSOFA for mortality in Brazil, focusing on sensitivity.Methods: We prospectively collected data from two cohorts of emergency department and ward patients. Cohort 1 included patients with suspected infection but without organ dysfunction or sepsis (22 hospitals: 3 public and 19 private). Cohort 2 included patients with sepsis (54 hospitals: 24 public and 28 private). The primary outcome was in-hospital mortality. The predictive accuracy of qSOFA was examined considering only the worst values before the suspicion of infection or sepsis.Measurements and Main Results: Cohort 1 contained 5,460 patients (mortality rate, 14.0%; 95% confidence interval [CI], 13.1-15.0), among whom 78.3% had a qSOFA score less than or equal to 1 (mortality rate, 8.3%; 95% CI, 7.5-9.1). The sensitivity of a qSOFA score greater than or equal to 2 for predicting mortality was 53.9% and the 95% CI was 50.3 to 57.5. The sensitivity was higher for a qSOFA greater than or equal to 1 (84.9%; 95% CI, 82.1-87.3), a qSOFA score greater than or equal to 1 or lactate greater than 2 mmol/L (91.3%; 95% CI, 89.0-93.2), and systemic inflammatory response syndrome plus organ dysfunction (68.7%; 95% CI, 65.2-71.9). Cohort 2 contained 4,711 patients, among whom 62.3% had a qSOFA score less than or equal to 1 (mortality rate, 17.3%; 95% CI, 15.9-18.7), whereas in public hospitals the mortality rate was 39.3% (95% CI, 35.5-43.3).Conclusions: A qSOFA score greater than or equal to 2 has low sensitivity for predicting death in patients with suspected infection in a developing country. Using a qSOFA score greater than or equal to 2 as a screening tool for sepsis may miss patients who ultimately die. Using a qSOFA score greater than or equal to 1 or adding lactate to a qSOFA score greater than or equal to 1 may improve sensitivity.Clinical trial registered with www.clinicaltrials.gov (NCT03158493).

Hysterectomy can be performed during sacrocolpopexy, but there are limited studies comparing the effect of route of hysterectomy on adverse events. We hypothesized there would be no difference in adverse events or patient-reported outcomes in women who underwent minimally invasive sacrocolpopexy with either vaginal or supracervical hysterectomy. This was a retrospective chart review with a cross-sectional survey component sent to all consenting patients. Patients were identified by procedure code for sacrocolpopexy and hysterectomy from January 2005 to June 2016. Of the 161 subjects meeting the inclusion criteria, 116 underwent supracervical and 45 vaginal hysterectomy. Overall incidence of perioperative adverse events was low. Vaginal hysterectomy cases were faster (276 vs. 324 min, p

Background The length of time between symptom onset and reperfusion therapy in patients with ST-segment elevation acute myocardial infarction (STEMI) is a key determinant of mortality. Information on this delay is scarce, particularly for developing countries. The objective of the study is to prospectively evaluate the individual components of reperfusion time (RT) in patients with STEMI treated at a University Hospital in 2012. Methods Medical records were reviewed to determine RT, its main (patient delay time [PDT] and system delay time [SDT]) and secondary components and hospital access variables. Cognitive responses were evaluated using a semi-structured questionnaire. Results A total of 50 patients with a mean age of 59 years (SD = 10.5) were included, 64% of whom were male. The median RT was 430 min, with an interquartile range of 315–750 min. Regarding the composition of RT in the sample, PDT corresponded to 18.9% and SDT to 81.1%. Emergency medical services were used in 23.5% of cases. Patients treated in intermediate care units showed a significant increase in SDT (p = 0.008). Regarding cognitive variables, PDT was approximately 40 min longer among those who answered “I didn’t think it was serious” (p = 0.024). Conclusions In a Brazilian tertiary public hospital, RT was higher than that recommended by international guidelines, mainly because of long SDT, which was negatively affected by time spent in intermediate care units. Emergency Medical Services underutilization was noted. A patient’s low perception of severity increased PDT. Electronic supplementary material The online version of this article (10.1186/s12913-018-3312-6) contains supplementary material, which is available to authorized users.

Background Systemic inflammation is associated with increased cognitive decline and risk for Alzheimer’s disease. Microglia (MG) activated during systemic inflammation can cause exaggerated neuroinflammatory responses and trigger progressive neurodegeneration. Dimethyl fumarate (DMF) is a FDA-approved therapy for multiple sclerosis. The immunomodulatory and anti-oxidant properties of DMF prompted us to investigate whether DMF has translational potential for the treatment of cognitive impairment associated with systemic inflammation. Methods Primary murine MG cultures were stimulated with lipopolysaccharide (LPS) in the absence or presence of DMF. MG cultured from nuclear factor (erythroid-derived 2)-like 2-deficient (Nrf2−/−) mice were used to examine mechanisms of DMF actions. Conditioned media generated from LPS-primed MG were used to treat hippocampal neuron cultures. Adult C57BL/6 and Nrf2−/− mice were subjected to peripheral LPS challenge. Acute neuroinflammation, long-term memory function, and reactive astrogliosis were examined to assess therapeutic effects of DMF. Results DMF suppressed inflammatory activation of MG induced by LPS. DMF suppressed NF-κB activity through Nrf2-depedent and Nrf2-independent mechanisms in MG. DMF treatment reduced MG-mediated toxicity towards neurons. DMF suppressed brain-derived inflammatory cytokines in mice following peripheral LPS challenge. The suppressive effect of DMF on neuroinflammation was blunted in Nrf2−/− mice. Importantly, DMF treatment alleviated long-term memory deficits and sustained reactive astrogliosis induced by peripheral LPS challenge. DMF might mitigate neurotoxic astrocytes associated with neuroinflammation. Conclusions DMF treatment might protect neurons against toxic microenvironments produced by reactive MG and astrocytes associated with systemic inflammation. Electronic supplementary material The online version of this article (10.1186/s12974-018-1125-5) contains supplementary material, which is available to authorized users.

OBJECTIVE The primary objective is to describe the long-term anatomic and subjective outcomes in women undergoing ventral rectopexy with sacrocolpo- or hysteropexy. The secondary objective is to describe the perioperative adverse events. METHODS This is a retrospective cohort of women who underwent ventral rectopexy with either concurrent sacrocolpo- or hysteropexy at a tertiary care center between 2009 and 2015. A composite outcome for recurrent pelvic organ prolapse and rectal prolapse was defined as subjective failure (vaginal or rectal prolapse symptoms), objective failure (prolapse to or beyond the hymen or full thickness rectal prolapse), or any retreatment for prolapse. Patient's Global Impression of Change was recorded at baseline and at all follow-up visits. Perioperative adverse events were defined a priori and collected up to 6 weeks after surgery. RESULT A total of 59 patients underwent a ventral rectopexy, either a sacrocolpopexy (48/59, 81.3%) or sacrohysteropexy (11/59, 18.6%). The median follow-up after surgery for all patients was 17 months (range, 1-76) with a composite success rate for both pelvic organ prolapse and rectal prolapse (estimated by Kaplan-Meier method) of 57.4%. Forty (91%) of 44 patients reported a Patient's Global Impression of Change score of 6 or 7, indicating significant improvement after surgery. Of the patients, 15 (25.4%) experienced a perioperative adverse event. Use of biologic graft was associated with a higher rate of adverse event (40.0% [95% confidence interval, 24.6-57.5] vs 10.3% [95% confidence interval, 3.6-26.3]; P < 0.01). CONCLUSIONS Ventral rectopexy with sacrocolpo- or hysteropexy is associated with significant improvement in anatomic and subjective outcomes. One in 4 women experienced a perioperative adverse event.

Study Objective To describe the multidisciplinary workup of pelvic organ prolapse and rectal prolapse or intussusception and to describe our technique of robotic ventral rectopexy and sacrocolpopexy. Design N/A. Setting N/A. Patients or Participants This is a patient with multi-compartment pelvic organ prolapse and rectal intussusception. Interventions The surgery is begun with the sacral dissection. The peritoneum is then opened in continuation along the right side of the rectum. Once the peritoneal reflection has been opened, it is carried down and further dissected from the posterior vagina. The deep pelvic dissection is then performed in the rectovaginal septum to the levator ani muscles, about five to six centimeters deep. Once the levator muscles are exposed, a ruler is introduced into the pelvis and the rectal width is measured. The anterior bladder dissection is then performed. A single sheet of flat, large pore, polypropylene mesh is then introduced and first secured to the levators bilaterally. Next the mesh is secured to the anterior rectum, sewing distal to proximal. This single sheet of mesh is then also used for the entire sacrocolpopexy by next securing the mesh to the posterior vagina. The mesh is then folded over the vaginal apex to the anterior vagina and before it is secured, the sacral tail is created by using the midportion of the mesh pulled out over the apex. The remaining steps of the procedure are completed in the same fashion as a standard sacrocolpopexy. Measurements and Main Results The patient had excellent anterior, apical, and posterior support with the use of a single flat sheet of lightweight mesh. The surgery had no complications with a minimal EBL. Conclusion Multidisciplinary treatment of concomitant pelvic organ and rectal prolapse by urogynecology and colorectal surgery allows for a safe and effective treatment of both conditions concurrently via a robotic ventral rectopexy and sacrocolpopexy with a single lightweight flat mesh sheet.

Purpose With prospective clinical sequencing of tumors emerging as a mainstay in cancer care, an urgent need exists for a clinical support tool that distills the clinical implications associated with specific mutation events into a standardized and easily interpretable format. To this end, we developed OncoKB, an expert-guided precision oncology knowledge base. Methods OncoKB annotates the biologic and oncogenic effects and prognostic and predictive significance of somatic molecular alterations. Potential treatment implications are stratified by the level of evidence that a specific molecular alteration is predictive of drug response on the basis of US Food and Drug Administration labeling, National Comprehensive Cancer Network guidelines, disease-focused expert group recommendations, and scientific literature. Results To date, > 3,000 unique mutations, fusions, and copy number alterations in 418 cancer-associated genes have been annotated. To test the utility of OncoKB, we annotated all genomic events in 5,983 primary tumor samples in 19 cancer types. Forty-one percent of samples harbored at least one potentially actionable alteration, of which 7.5% were predictive of clinical benefit from a standard treatment. OncoKB annotations are available through a public Web resource ( http://oncokb.org ) and are incorporated into the cBioPortal for Cancer Genomics to facilitate the interpretation of genomic alterations by physicians and researchers. Conclusion OncoKB, a comprehensive and curated precision oncology knowledge base, offers oncologists detailed, evidence-based information about individual somatic mutations and structural alterations present in patient tumors with the goal of supporting optimal treatment decisions.

For patients with rectal prolapse undergoing Ventral Rectopexy (VR), the impact of prior prolapse surgery on prolapse recurrence is not well described. The purpose of this study was to compare recurrence rates after VR in patients undergoing primary and repeat rectal prolapse repairs. This study is a prospective cohort study. IRB-approved prospective data registry of consecutive patients undergoing VR for full-thickness external rectal prolapse between 2009 and 2015. Rectal prolapse recurrence was defined as either external prolapse through the anal sphincters or symptomatic rectal mucosa prolapse warranting additional surgery. Preoperative and postoperative morbidity and functional outcomes were analyzed. Actuarial recurrence rates were calculated using the Kaplan-Meier method. A total of 108 VRs were performed during the study period. Seventy-two were primary and 36 repeat repairs. Seven cases were open, 23 laparoscopic, and 78 robotic. Six cases were converted from laparoscopic/robotic to open. In 63 patients, VR was combined with gynecological procedures. There were no statistical differences between primary or recurrent prolapse for the following: demographics, operative time, concomitant gynecologic procedures, complications, blood loss, and graft material type. Length of stay was longer in patients with a history of prior prolapse surgery (p = 0.01). Prolapse recurrence rates for primary repairs were reported at 1.4, 6.9, and 9.7% and for recurrent prolapse procedures 13.9, 25, and 25% at 1, 3, and 5 years (p = 0.13). Mean length of follow-up was similar between groups. Time to recurrence was significantly shorter in patients undergoing repeat prolapse surgery 8.8 vs 30.7 months (p = 0.03). VR is a better option for patients undergoing primary rectal prolapse repair.

Orofacial injuries are common in sports activities and may vary in complexity and the tissues involved. Most sports-related trauma occurs when a player hits another player, an object or the ground. This report presents a case of an injury caused by a punchlike blow to the face during a handball college team practice session. The patient suffered a traumatic blow to the left side of the nose and mouth and promptly attended a dentist. After a clinical examination and a CBCT scan, the following injuries were diagnosed: upper lip laceration, upper left lateral incisor subluxation and anterior nasal spine fracture. More severe teeth injuries were likely prevented because the patient was wearing a mouthguard.

Cerebral ischemic stroke accounts for more than 80% of all stroke cases. During cerebral ischemia, reactive oxygen species produced in brain tissue induce oxidative stress and inflammatory responses. D3T, the simplest compound of the cyclic, sulfur-containing dithiolethiones, is found in cruciferous vegetables and has been reported to induce antioxidant genes and glutathione biosynthesis through activation of Nrf2. In addition to antioxidant activity, D3T was also reported to possess anti-inflammatory effects. In this study, we evaluated the therapeutic potential of D3T for the treatment of ischemic stroke and investigated the mechanisms underlying the protective effects of D3T in ischemic stroke. Mice subjected to transient middle cerebral artery occlusion/reperfusion (tMCAO/R) were administered with vehicle or D3T to evaluate the effect of D3T in cerebral brain injury. We observed D3T reduced infarct size, decreased brain edema, lessened blood-brain barrier disruption, and ameliorated neurological deficits. Further investigation revealed D3T suppressed microglia (MG) activation and inhibited peripheral inflammatory immune cell infiltration of CNS in the ischemic brain. The protective effect of D3T in ischemic stroke is mediated through Nrf2 induction as D3T-attenuated brain injury was abolished in Nrf2 deficient mice subjected to tMCAO/R. In addition, in vitro results indicate the induction of Nrf2 by D3T is required for its suppressive effect on MG activation and cytokine production. In summary, we demonstrate for the first time that D3T confers protection against ischemic stroke, which is mediated through suppression of MG activation and inhibition of CNS peripheral cell infiltration, and that the protective effect of D3T in ischemic stroke is dependent on the activation of Nrf2.

BACKGROUND Severe labial agglutination can be refractory to outpatient management and can lead to voiding dysfunction in postmenopausal women. Labial agglutination is often a sequela of long-standing inflammatory processes, which include untreated lichen planus, lichen sclerosus, and atrophic vaginitis. CASE An 82-year-old parous woman presented with severe labial agglutination and complete obstruction of her vaginal introitus, causing obstructive voiding symptoms. She underwent a surgical procedure to release the fused labia. Pathologic evaluation of a vulvar biopsy revealed nephrogenic adenoma, which is an uncommon benign lesion usually presenting in the urinary tract. CONCLUSIONS Refractory, severe labial agglutination in postmenopausal women can lead to significant voiding dysfunction, and the underlying chronic inflammation may result in pathologic changes such as nephrogenic adenoma. Pathologic tissue diagnosis is important to plan appropriate surveillance for patients with this chronic condition.

Clonal hematopoiesis (CH) is frequent in cancer patients and associated with increased risk of therapy related myeloid neoplasms (tMN). To define the relationship between CH, oncologic therapy, and tMN progression, we studied 24,439 cancer patients. We show that previously treated patients have increased rates of CH, with enrichment of mutations in DNA Damage Response (DDR) genes (TP53, PPM1D, CHEK2). Exposure to radiation, platinum and topoisomerase II inhibitors have the strongest association with CH with evidence of dose-dependence and gene-treatment interactions. We validate these associations in serial sampling from 525 patients and show that exposure to cytotoxic and radiation therapy imparts a selective advantage specifically in hematopoietic cells with DDR mutations. In patients who progressed to tMN, the clone at CH demarcated the dominant clone at tMN diagnosis. CH mutational features predict risk of therapy-related myeloid neoplasm in solid tumor patients with clinical implications for early detection and treatment decisions.

Introdução: A ventilação não invasiva (VNI) apresenta benefícios comprovados em diversas condições clínicas, entretanto, os resultados em pacientes com câncer são controversos. Objetivos: Analisar os fatores preditores para falha da VNI em pacientes oncológicos; descrever a mortalidade hospitalar e a sobrevida global após internação. Método: Estudo de coorte retrospectiva incluindo pacientes com tumores sólidos e neoplasias hematológicas, admitidos para internação hospitalar no Hospital do Câncer I do Instituto Nacional de Câncer José Alencar Gomes da Silva (HC I/INCA), entre 1º de janeiro e 31 de dezembro de 2017, e que foram submetidos à VNI. A associação entre as variáveis de exposição (variáveis clínicas e sociodemográficas) e os desfechos (falha na VNI) foi realizada pela regressão logística bruta e ajustada. Foi utilizado o método de Kaplan-Meier para análise da sobrevida global. Resultados: Foram incluídos 66 pacientes com média de idade de 62,3 anos (±15,0). O tempo médio de VNI na primeira sessão foi de 49,8 minutos (±30,9); o número médio de sessões foi de 2,1 (±1,4). Os pacientes que apresentaram falha tiveram maior tempo de internação hospitalar (11,8 dias vs 6,0 dias) e maior mortalidade hospitalar (90,9 vs 43,6%). Os pacientes com infecção pulmonar tiveram um risco de 4,71 vezes maior de falharem na VNI, em relação àqueles pacientes que apresentaram sucesso (OR 4,71; IC 95%, 1,14-19,47; p=0,032). Conclusão: Pacientes que apresentaram infecção pulmonar tiveram maior probabilidade em falhar na VNI. Foi observada pior sobrevida global entre aqueles pacientes que falharam na VNI.

Radiographic examinations complement the anamnesis and physical exam with the purpose of reaching diagnosis, prognosis and treatment planning. In this case report, a 48 year-old male Caucasian patient was referred to an oral and maxillofacial surgeon by a general practitioner after a panoramic radiography for treatment planning; the implant surgery follow-up portrayed a multilocular radiolucent image at the left posterior mandible. Based solely on the panoramic radiography, the diagnostic hypothesis was ameloblastoma. The surgeon decided to perform an incisional biopsy. However, during the procedure, the professional noted that the lesion was easily detached from the adjacent bone and opted for the total removal of the lesion, thus altering its diagnostic hypothesis to central ossifying fibroma (COF). The histopathological result confirmed the diagnostic hypothesis provided by the surgeon, i.e. COF. Although multilocular presentation is not common, COF should be considered in the scope of multilocular radiolucent lesions of the jaws. In addition, computerized tomography imaging exam complemented by surgical and histopathological aspects should be considered for establishing the final diagnosis and conducting the therapeutic approach.

© 2019 Valls, Cambray, Pérez-Guallar, Bozic, Bermúdez-López, Fernández, Betriu, Rodríguez and Valdivielso., Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2,445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionization– time of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD., The NEFRONA study was funded by a research grant from AbbVie, FEDER funds and the Instituto de Salud Carlos III RETIC (RD16/0009), FIS PI16/01354, and PI10/00173. IR was financially supported by Fundación para el Fomento en Asturias de la Investigación Cientfica Aplicada y la Tecnología (FICYT).

Background: Pheochromocytoma and paraganglioma (PHEO/PGL) are rare neuroendocrine tumors which may cause potentially life-threatening complications, with about a third of cases found to harbor specific gene mutations. Thus, early diagnosis, treatment, and meticulous monitoring are of utmost importance. Because of low incidence of succinate dehydrogenase complex subunit A (SDHA)-related metastatic PHEO/PGL, currently there exists insufficient clinical information, especially with regards to its diagnostic and treatment characteristics. Methods: Ten patients with SDHA-related metastatic PHEO/PGL were followed-up prospectively and/or retrospectively between January 2010-July 2018. They underwent biochemical tests (n = 10), 123I-MIBG (n = 9) scintigraphy, and multiple whole-body positron emission tomography/computed tomography (PET/CT) scans with 68Ga-DOTATATE (n = 10), 18F-FDG (n = 10), and 18F-FDOPA (n = 6). Results: Our findings suggest that these tumors can occur early and at extra-adrenal locations, behave aggressively, and have a tendency to develop metastatic disease within a short period of time. None of our patients had a family history of PHEO/PGL, making them appear sporadic. Nine out of 10 patients showed abnormal PHEO/PGL-specific biochemical markers with predominantly noradrenergic and/or dopaminergic phenotype, suggesting their utility in diagnosing and monitoring the disease. Per patient detection rates of 68Ga-DOTATATE (n = 10/10), 18F-FDG (n = 10/10), 18F-FDOPA (n = 5/6) PET/CT, and 123I-MIBG (n = 7/9) scintigraphy were 100, 100, 83.33, and 77.77%, respectively. Five out of 7 123I-MIBG positive patients had minimal 123I-MIBG avidity or detected very few lesions compared to widespread metastatic disease on 18F-FDG PET/CT, implying that diagnosis and treatment with 123/131I-MIBG is not a good option. 68Ga-DOTATATE PET/CT was found to be superior or equal to 18F-FDG PET/CT in 7 out of 10 patients and hence, is recommended for evaluation and follow-up of these patients. All 7 out of 7 patients who received conventional therapies (chemotherapy, somatostatin analog therapy, radiation therapy, 131I-MIBG, peptide receptor radionuclide therapy) in addition to surgery showed disease progression. Conclusion: In our cohort of patients, SDHA-related metastatic PHEO/PGL followed a disease-course similar to that of SDHB-related metastatic PHEO/PGL, showing highly aggressive behavior, similar imaging and biochemical phenotypes, and suboptimal response to conventional therapies. Therefore, we recommend careful surveillance of the affected patients and a search for effective therapies.

Summary Background In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events. Methods PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901. Findings 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3–8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93–1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group. Interpretation The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months. Funding The French National Cancer Institute.

Background: Iron deficiency (ID) and anaemia are frequent in Heart Failure (HF) patients, but there are few data about its prevalence and prognosis in elderly HF patients with preserved ejection fraction (HF-PEF). Aim: The aim of this study is to ascertain if ID alone or associated with anaemia is related to negative clinical outcomes in elderly patients with HF-PEF. Design/Methods: 139 consecutive patients discharged from our Internal Medicine Department with a diagnosis of HF-PEF from June 2011 to June 2014 were followed up until June 2015. All demographic and clinical data, echocardiography, biochemical parameters, treatment at discharge, new hospital admissions and death were registered in a specific database. Results: Mean age was 79.1 years (SD 8.3 years), and 94 (67.6%) were women. Anaemia was present in 85 (61%), any iron deficiency in 92 (67%) and absolute iron deficiency in 67 (48%) of these patients. 33 patients (23%) died during a mean follow-up of 649 days. Increased mortality was related to age, previous hospital admissions, lower albumin level, lower Barthel score, and higher ferritin level. Using a composite endpoint of HF readmission or death during first year after index admission, 54 patients (38.8%) had this negative outcome. Lower Barthel Score and albumin values, higher NT pro-BNP and ferritin level, and absence of iron deficiency, were related to this negative outcome. Conclusion: Anaemia and Iron Deficiency are usual findings in our elderly HF-PEF patients, but only a high level of serum ferritin was associated with worse outcomes in this setting.

Given the accelerating opioid crisis in the United States and evidence that patients use fewer opioid tablets than prescribed, surgeons may choose to decrease prescribed quantities. The effect this may have on patient satisfaction with pain control after hospital discharge is unknown.The primary objective of this study was to compare patient satisfaction with postoperative pain control between patients receiving a routine or reduced quantity opioid prescription after prolapse repair. Secondary objectives included a comparison of opioid-related side-effects, the number of opioid tablets used, and the number of excess tablets prescribed between these groups.This was a single-center, unmasked, 2-arm, randomized controlled noninferiority trial of women who underwent a prolapse repair with a planned overnight hospitalization. Patients were assigned randomly to 1 of 2 study arms: routine (28 tablets of oxycodone 5 mg) or reduced (5 tablets) prescription of opioid tablets. Patients were eligible if they were at least 18 years of age and undergoing a prolapse repair with an anticipated overnight hospital stay. Exclusion criteria included a history of chronic pain, preoperative opioid use, intolerance to study medication, or a score of ≥30 on the Pain Catastrophizing Scale. In addition to their opioid prescription, all patients received multimodal pain medications at discharge. Patients were asked to complete 6 weeks of diaries to record pain and medication use. The primary outcome (patient satisfaction) was collected as part of a postoperative survey completed at patients' routine postoperative visit 6 weeks after surgery. The sample size for noninferiority was calculated at 59 patients per group for a total of 118 patients.One hundred eighteen patients were assigned randomly; the primary outcome was available for 116. The majority of patients were white, postmenopausal, and nonsmokers; the mean age was 62±10.4 years. The most common surgery was a hysterectomy with native tissue repair (n=71; 60%). One hundred ten patients (93%) were satisfied with postoperative pain control. Statistical analysis constructed for noninferiority showed that the difference between the groups was15% (93% vs 93%; P=.005). Subjects in the reduced arm reported requiring an additional opioid prescription more frequently than in the routine arm (15% vs 2%; P=.01). Patients in the routine arm used more opioid tablets than the reduced arm (median, 3 [interquartile range, 0-14] vs 1 [interquartile range, 0-3]), but overall opioid utilization was low. As such, patients in the routine arm had significantly more unused opioid tablets (median, 26 [interquartile range, 15-28] vs 4 [interquartile range, 2-5]).Patient satisfaction with pain control was noninferior in patients who received a reduced quantity of opioid tablets after prolapse repair compared with those who received a routine prescription. A large quantity of excess opioid tablets was seen in both groups. Surgeons should consider prescribing 5-10 opioid tablets after prolapse repair surgery and consider applying these findings to postoperative prescribing after other gynecologic procedures.

Recent studies among healthy individuals show evidence of somatic mutations in leukemia-associated genes, referred to as clonal hematopoiesis (CH). To determine the relationship between CH and oncologic therapy we collected sequential blood samples from 525 cancer patients (median sampling interval time = 23 months, range: 6-53 months) of whom 61% received cytotoxic therapy or external beam radiation therapy and 39% received either targeted/immunotherapy or were untreated. Samples were sequenced using deep targeted capture-based platforms. To determine whether CH mutational features were associated with tMN risk, we performed Cox proportional hazards regression on 9,549 cancer patients exposed to oncologic therapy of whom 75 cases developed tMN (median time to transformation=26 months). To further compare the genetic and clonal relationships between tMN and the proceeding CH, we analyzed 35 cases for which paired samples were available. We compared the growth rate of the variant allele fraction (VAF) of CH clones across treatment modalities and in untreated patients. A significant increase in the growth rate of CH mutations was seen in DDR genes among those receiving cytotoxic (p=0.03) or radiation therapy (p=0.02) during the follow-up period compared to patients who did not receive therapy. Similar growth rates among treated and untreated patients were seen for non-DDR CH genes such as DNMT3A. Increasing cumulative exposure to cytotoxic therapy (p=0.01) and external beam radiation therapy (2x10-8) resulted in higher growth rates for DDR CH mutations. Among 34 subjects with at least two CH mutations in which one mutation was in a DDR gene and one in a non-DDR gene, we studied competing clonal dynamics for multiple gene mutations within the same patient. The risk of tMN was positively associated with CH in a known myeloid neoplasm driver mutation (HR=6.9, p Citation Format: Kelly L. Bolton, Ryan N. Ptashkin, Teng Gao, Lior Braunstein, Sean M. Devlin, Minal Patel, Antonin Berthon, Aijazuddin Syed, Mariko Yabe, Catherine Coombs, Nicole M. Caltabellotta, Mike Walsh, Ken Offit, Zsofia Stadler, Choonsik Lee, Paul Pharoah, Konrad H. Stopsack, Barbara Spitzer, Simon Mantha, James Fagin, Laura Boucai, Christopher J. Gibson, Benjamin Ebert, Andrew L. Young, Todd Druley, Koichi Takahashi, Nancy Gillis, Markus Ball, Eric Padron, David Hyman, Jose Baselga, Larry Norton, Stuart Gardos, Virginia Klimek, Howard Scher, Dean Bajorin, Eder Paraiso, Ryma Benayed, Maria Arcilla, Marc Ladanyi, David Solit, Michael Berger, Martin Tallman, Montserrat Garcia-Closas, Nilanjan Chatterjee, Luis Diaz, Ross Levine, Lindsay Morton, Ahmet Zehir, Elli Papaemmanuil. Oncologic therapy shapes the fitness landscape of clonal hematopoiesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5703.

With the introduction of the new meningitis A conjugate vaccine in 2012, Benin has opted for case-by-case surveillance for bacterial meningitis. The study aims to assess the case-by-case surveillance system for the meningitis epidemic in Benin during the period 2016 to 2018. A retrospective and evaluative study with a mixed approach (qualitative and quantitative) was conducted, on the three sites identified for sentinel surveillance of meningitis in Benign. The evaluation of the performance of the surveillance system was based on the updated guidelines of the Center for Disease Prevention and Control to evaluate a public health surveillance system. All criteria except sensitivity, specificity and positive predictive value were measured. Semi-structured individual interviews were conducted with the agents of the surveillance system surveyed and the normative documents as well as the notice forms were examined. This study reveals that all the centers had the case definition and notification forms. The ratio of notified cases to registered cases was 0.77. We found that the monitoring system in place had five levels. The system performance was recognized with simplicity at 80.8%, good acceptability (completeness: 98.5%; Promptitude: 88.9%) and responsiveness of 85%. The completeness of the health facilities was 45%. This study shows that it is imperative to strengthen the knowledge of the actors involved in epidemiological surveillance through periodic training to improve the performance of the surveillance system.

Genitourinary syndrome of menopause is defined as the collection of signs and symptoms of the genitourinary tract from menopause, previously known as vulvovaginal atrophy. The Food and Drug Administration has approved select hormonal and nonhormonal treatment for vaginal atrophy, including systemic estrogen, vaginal estrogen, estrogen receptor modulators, and dehydroepiandrosterone. These medications can increase the risk of thromboembolic disease and malignancy; furthermore, the cost of the medications have been increasing. Energy-based therapy such as the fractional CO2 laser energy or nonablative photothermal Erbium:YAG-laser has emerged as an alternative treatment option for genitourinary syndrome of menopause. However, in July of 2018, the Food and Drug Administration released a statement cautioning women against vaginal rejuvenation devices and highlighted the paucity of long-term clinical research in this field. This statement may result in patients' hesitation to seek care for genitourinary syndrome of menopause. These recent events should be a call to action to urge physicians to address the barriers that exist in the treatment of genitourinary syndrome of menopause because of limited clinical research, cost of treatment, and fear.

Malignant transformation can result in melanoma cells that resemble different stages of their embryonic development. Our gene expression analysis of human melanoma cell lines and patient tumors revealed that melanoma follows a two-dimensional differentiation trajectory that can be subclassified into four progressive subtypes. This differentiation model is associated with subtype-specific sensitivity to iron-dependent oxidative stress and cell death known as ferroptosis. Receptor tyrosine kinase-mediated resistance to mitogen-activated protein kinase targeted therapies and activation of the inflammatory signaling associated with immune therapy involves transitions along this differentiation trajectory, which lead to increased sensitivity to ferroptosis. Therefore, ferroptosis-inducing drugs present an orthogonal therapeutic approach to target the differentiation plasticity of melanoma cells to increase the efficacy of targeted and immune therapies.

Xanthohumol (XN), a prenylated flavonoid from hops, improves dysfunctional glucose and lipid metabolism in animal models of metabolic syndrome (MetS). However, its metabolic transformation into the estrogenic metabolite, 8-prenylnaringenin (8-PN), poses a potential health concern for its use in humans. To address this concern, we evaluated two hydrogenated derivatives, α,β-dihydro-XN (DXN) and tetrahydro-XN (TXN), which showed negligible affinity for estrogen receptors α and β, and which cannot be metabolically converted into 8-PN. We compared their effects to those of XN by feeding C57BL/6J mice a high-fat diet (HFD) containing XN, DXN, or TXN for 13 weeks. DXN and TXN were present at higher concentrations than XN in plasma, liver and muscle. Mice administered XN, DXN or TXN showed improvements of impaired glucose tolerance compared to the controls. DXN and TXN treatment resulted in a decrease of HOMA-IR and plasma leptin. C2C12 embryonic muscle cells treated with DXN or TXN exhibited higher rates of uncoupled mitochondrial respiration compared to XN and the control. Finally, XN, DXN, or TXN treatment ameliorated HFD-induced deficits in spatial learning and memory. Taken together, DXN and TXN could ameliorate the neurocognitive-metabolic impairments associated with HFD-induced obesity without risk of liver injury and adverse estrogenic effects.

© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Viral meningitis is increasingly recognised, but little is known about the frequency with which it occurs, or the causes and outcomes in the UK. We aimed to determine the incidence, causes, and sequelae in UK adults to improve the management of patients and assist in health service planning. Methods: We did a multicentre prospective observational cohort study of adults with suspected meningitis at 42 hospitals across England. Nested within this study, in the National Health Service (NHS) northwest region (now part of NHS England North), was an epidemiological study. Patients were eligible if they were aged 16 years or older, had clinically suspected meningitis, and either underwent a lumbar puncture or, if lumbar puncture was contraindicated, had clinically suspected meningitis and an appropriate pathogen identified either in blood culture or on blood PCR. Individuals with ventricular devices were excluded. We calculated the incidence of viral meningitis using data from patients from the northwest region only and used these data to estimate the population-standardised number of cases in the UK. Patients self-reported quality-of-life and neuropsychological outcomes, using the EuroQol EQ-5D-3L, the 36-Item Short Form Health Survey (SF-36), and the Aldenkamp and Baker neuropsychological assessment schedule, for 1 year after admission. Findings: 1126 patients were enrolled between Sept 30, 2011, and Sept 30, 2014. 638 (57%) patients had meningitis: 231 (36%) cases were viral, 99 (16%) were bacterial, and 267 (42%) had an unknown cause. 41 (6%) cases had other causes. The estimated annual incidence of viral meningitis was 2·73 per 100 000 and that of bacterial meningitis was 1·24 per 100 000. The median length of hospital stay for patients with viral meningitis was 4 days (IQR 3–7), increasing to 9 days (6–12) in those treated with antivirals. Earlier lumbar puncture resulted in more patients having a specific cause identified than did those who had a delayed lumbar puncture. Compared with the age-matched UK population, patients with viral meningitis had a mean loss of 0·2 quality-adjusted life-years (SD 0·04) in that first year. Interpretation: Viruses are the most commonly identified cause of meningitis in UK adults, and lead to substantial long-term morbidity. Delays in getting a lumbar puncture and unnecessary treatment with antivirals were associated with longer hospital stays. Rapid diagnostics and rationalising treatments might reduce the burden of meningitis on health services. Funding: Meningitis Research Foundation and UK National Institute for Health Research.