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Objective To develop prediction models for intensive care unit (ICU) vs non-ICU level-of-care need within 24 hours of inpatient admission for emergency department (ED) patients using electronic health record data. Materials and Methods Using records of 41 654 ED visits to a tertiary academic center from 2015 to 2019, we tested 4 algorithms—feed-forward neural networks, regularized regression, random forests, and gradient-boosted trees—to predict ICU vs non-ICU level-of-care within 24 hours and at the 24th hour following admission. Simple-feature models included patient demographics, Emergency Severity Index (ESI), and vital sign summary. Complex-feature models added all vital signs, lab results, and counts of diagnosis, imaging, procedures, medications, and lab orders. Results The best-performing model, a gradient-boosted tree using a full feature set, achieved an AUROC of 0.88 (95%CI: 0.87–0.89) and AUPRC of 0.65 (95%CI: 0.63–0.68) for predicting ICU care need within 24 hours of admission. The logistic regression model using ESI achieved an AUROC of 0.67 (95%CI: 0.65–0.70) and AUPRC of 0.37 (95%CI: 0.35–0.40). Using a discrimination threshold, such as 0.6, the positive predictive value, negative predictive value, sensitivity, and specificity were 85%, 89%, 30%, and 99%, respectively. Vital signs were the most important predictors. Discussion and Conclusions Undertriaging admitted ED patients who subsequently require ICU care is common and associated with poorer outcomes. Machine learning models using readily available electronic health record data predict subsequent need for ICU admission with good discrimination, substantially better than the benchmarking ESI system. The results could be used in a multitiered clinical decision-support system to improve ED triage.

Limited professional development training exists for chief residents. The available training uses in-person lectures and workshops at annual national conferences. The COVID-19 pandemic prevented most in-person gatherings in 2020, including pivotal onboarding and training events for new chief residents. However, for the last five years, Academic Life in Emergency Medicine's Chief Resident Incubator conducted year-long remote training programs, creating virtual communities of practice for chief residents in emergency medicine (EM). As prior leaders and alumni from the Incubator, we sought to respond to the limitations presented by the pandemic and create an onboarding event to provide foundational knowledge for incoming chief residents. We developed a half-day virtual conference, whereupon 219 EM chief residents enrolled. An effective professional development experience is feasible and scalable using online videoconferencing technologies, especially if constructed with content expertise, psychological safety, and production design in mind.RéSUMé: Il existe une formation de développement professionnel limitée pour les résidents en chef. La formation disponible utilise des conférences et des ateliers en personne lors de conférences nationales annuelles. La pandémie de COVID-19 a empêché la plupart des rassemblements en personne en 2020, y compris des activités d’intégration et de formation essentielles pour les nouveaux résidents en chef. Cependant, au cours des cinq dernières années, l'incubateur des résidents en chef de Academic Life in Emergency Medicine a organisé des programmes de formation à distance d'un an, créant ainsi des communautés de pratique virtuelles pour les résidents en chef en médecine d'urgence (MU). En tant qu'anciens dirigeants et anciens de l'incubateur, nous avons cherché à répondre aux limites présentées par la pandémie et à créer un événement d'intégration pour fournir des connaissances fondamentales aux nouveaux résidents en chef. Nous avons mis au point une conférence virtuelle d'une demi-journée, à laquelle 219 résidents en chef de MU se sont inscrits. Une expérience de développement professionnel efficace est réalisable et évolutive grâce aux technologies de vidéoconférence en ligne, surtout si elle est construite en tenant compte de l'expertise du contenu, de la sécurité psychologique et de la conception de la production.

Introduction The World Health Organization's (WHO's) Basic Emergency Care (BEC) course was developed to address training gaps in low- and middle-income countries (LMICs). Simultaneously, LMICs have experienced an unprecedented increase in the number of cell phone and internet users. We developed a mobile application adjunct to the BEC course (BEC app) and sought to assess the reach of the BEC app. Methods Forty-six BEC course participants, made up of doctors and nurses from three hospital sites in Tanzania, were given access to the BEC app with download instructions. Moderators tracked mobile access characteristics and barriers. This is a descriptive study outlining the implementation of the BEC app and associated findings from the process. Results Fewer than 10% of participants were able to independently download and use the application. The download process revealed three key barrier areas: accessibility (no smartphone, smartphone without charge, no access to data/WiFi to download app, increased cost of data), technical (outdated operating system, inconsistent access to data/WiFi to run the app, insufficient phone storage), and participant-related characteristics (variability in smartphone literary, language discordance, smartphone turnover). Of the 46 participants, 29 (63%) were able to download and use the BEC app successfully with moderator support. Conclusions There is potential utility of mobile health in LMICs. However, barriers still exist to reaching the largest possible audience for these initiatives. The importance of app compatibility with a broad range of operating systems and limitation of the amount of data needed to download and use the app was underscored by our study. Moreover, creative solutions are needed to facilitate large-scale roll-outs of mobile health interventions, such as a distribution model that relies on super user and peer support rather than an individual moderator. Additional local perspectives on the download process and the utilisation and acceptance of the application post-implementation are needed.

Der Begriff nichtmelanozytare Hauttumoren fasst das Basalzellkarzinom und das Plattenepithelkarzinom zusammen. Sie sind bei Weitem die haufigsten malignen Tumoren der kaukasischen Bevolkerung mit steigender Inzidenz. Die deutschen Leitlinien zur Diagnostik und Therapie beider Hauttumoren machen Angaben zur Histopathologie, die in relevanten Punkten dargestellt werden sollen. Der Beitrag beruht auf den Inhalten der aktuellen Leitlinien, einer selektiven Literaturrecherche und eigenen Fallbeispielen. Bei klinischem Verdacht auf einen der Tumoren ist die histopathologische Diagnose anzustreben. Dies gelingt meist an der Hamatoxylin-Eosin-Standardfarbung, und nur selten sind immunhistologische Untersuchungen indiziert. Standardtherapie ist die Exzision mit histologischer Beurteilung der Schnittrander. Beim Basalzellkarzinom wird ein Low- und High-Grade-Wachstumsmuster unterschieden, wobei der High-Grade-Typ oft eine klinisch nur schwer abzuschatzende Ausdehnung aufweist. Beim kutanen Plattenepithelkarzinom werden mehrere Varianten unterschieden. Insbesondere das desmoplastische Plattenepithelkarzinom weist eine erhohte Rezidiv- und Metastasierungsrate auf. Wichtiger histologischer Prognosefaktor des Plattenepithelkarzinoms ist die Tumordicke. Eine perineurale Invasion und eine geringe Differenzierung sind mit einer schlechteren Prognose assoziiert. In besonderen Fallen kann die Zuordnung einer Hautinfiltration eines Karzinoms schwierig sein. Eine innovative molekularpathologische Methode stellt die genomweite DNA-Methylierung dar. Anhand eines Beispiels wird dargestellt, dass die sichere Diagnose einer ungewohnlichen Metastase eines Mammakarzinoms mit plattenepithelialer Differenzierung in der Haut moglich war.

International audience; Hereditary xerocytosis is a dominantly inherited red cell membrane disorder caused in most cases by gain-of-function mutations in PIEZO1, encoding a mechanosensitive ion channel that translates a mechanic stimulus into calcium influx. We found that PIEZO1 was expressed early in erythroid progenitor cells, and investigated whether it could be involved in erythropoiesis, besides having a role in the homeostasis of mature red cell hydration. In UT7 cells, chemical PIEZO1 activation using YODA1 repressed glycophorin A expression by 75%. This effect was PIEZO1-dependent since it was reverted using specific short hairpin-RNA knockdown. The effect of PIEZO1 activation was confirmed in human primary progenitor cells, maintaining cells at an immature stage for longer and modifying the transcriptional balance in favor of genes associated with early erythropoiesis, as shown by a high GATA2/GATAI ratio and decreased alpha/beta-globin expression. The cell proliferation rate was also reduced, with accumulation of cells in G0/G1 of the cell cycle. The PIEZO1-mediated effect on UT7 cells required calcium-dependent activation of the NFAT and ERK1/2 pathways. In primary erythroid cells, PIEZO1 activation synergized with erythropoietin to activate STATS and ERK, indicating that it may modulate signaling pathways downstream of erythropoietin receptor activation. Finally, we studied the in-vitro erythroid differentiation of primary cells obtained from 14 PIEZO1-mutated patients, from 11 families, carrying ten different mutations. We observed a delay in erythroid differentiation in all cases, ranging from mild (n=3) to marked (n=8). Overall, these data demonstrate a role for PIEZO1 during erythropoiesis, since activation of PIEZO1 both chemically and through activating mutations - delays erythroid maturation, providing new insights into the pathophysiology of hereditary xerocytosis.

Congenital sideroblastic anaemia (CSA) is a rare disease caused by germline mutations of genes involved in haem and iron-sulphur cluster formation, and mitochondrial protein biosynthesis. We performed a retrospective multicentre European study of a cohort of childhood-onset CSA patients to explore genotype/phenotype correlations. We studied 23 females and 20 males with symptoms of CSA. Among the patients, the most frequently mutated genes were ALAS2 (n = 10; 23·3%) and SLC25A38 (n = 8; 18·6%), causing isolated forms of microcytic anaemia of varying severity. Five patients with SLC19A2 mutations suffered from thiamine-responsive megaloblastic anaemia and three exhibited the 'anaemia, deafness and diabetes' triad. Three patients with TRNT1 mutations exhibited severe early onset microcytic anaemia associated with thrombocytosis, and two exhibited B-cell immunodeficiency, inflammatory syndrome and psychomotor delay. The prognoses of patients with TRNT1 and SLC2A38 mutations were generally dismal because of comorbidities or severe iron overload. No molecular diagnosis could be established in 14/43 cases. This study emphasizes the frequency of ALAS2 and SLC25A38 mutations and provides the largest comprehensive analysis to date of genotype/phenotype correlations in CSA. Further studies of CSA patients with data recorded in an international registry would be helpful to improve patient management and establish standardized guidelines.

International audience

Accurate classification of melanocytic proliferations has important implications for prognostic prediction, treatment and follow-up. Although most melanocytic proliferations can be accurately classified using clinical and pathological criteria, classification (specifically distinction between nevus and melanoma) can be challenging in a subset of cases, including those with spitzoid morphology. Genetic studies have shown that mutation profiles differ between primary melanoma subtypes and Spitz nevi. These differences may aid in distinguishing benign from malignant in some melanocytic tumours. Here, we present a selection of melanocytic proliferations with equivocal histopathological criteria, wherein genetic analysis was requested to help guide classification. In two of four cases, the genetic results offered valuable insights, allowing a definitive diagnosis, indicating the diagnostic value of mutation profiling in a real-world routine clinical setting. Although histopathological assessment remains decisive in melanocytic proliferation classification, we recommend including genetic profiling in cases of borderline or atypical lesion to support accurate classification.

Background Neratinib is approved in the European Union for extended adjuvant treatment of human epidermal growth factor receptor 2–positive/hormone receptor–positive (copositive) early breast cancer ≤1 year of completion of prior trastuzumab-based therapy. Here, we report analyses of the hormone receptor–positive subgroup (N = 1631) from the ExteNET trial performed for the German health technology assessment (HTA). Results With 2 years of median follow-up, HTA analyses revealed a significant advantage in disease-free survival (DFS) for neratinib vs. placebo (absolute/relative risk reduction: 4.1/48.2%; hazard ratio [HR] [95% confidence interval {CI}]: 0.45 [0.29; 0.69]; p = 0.0002), consistent with distant DFS (absolute/relative risk reduction: 3.1/46.3%; HR [95% CI]: 0.52 [0.32; 0.84]; p = 0.0082). The 5-year follow-up confirmed this outcome.Quality of life analyses did not show clinically relevant differences over all time points. Only at month 1, the Functional Assessment of Cancer Therapy – General total score revealed a statistically relevant difference to the disadvantage of neratinib classified as clinically relevant. The tolerability profile of neratinib was dominated by gastrointestinal events, mainly diarrhoea (all grades: 94.4%; grade III: 39.4%; no systematic antidiarrhoeal prophylaxis), nausea (all grades/grade III: 43.9/1.6%), vomiting (26.6/3.2%), abdominal pain (23.8/1.9%), fatigue (28.1/1.9%) and rash (14.3/0.4%). No cumulative or irreversible toxicities were observed. As shown in the CONTROL study and instituted via a risk management plan, diarrhoea management can reduce frequency, cumulative duration and severity of diarrhoea. Conclusion Extended adjuvant neratinib provides a clinically relevant benefit with further incremental reduction of relapse risk in the curative setting. Accordingly, the German HTA authority has granted an added benefit for this new treatment option.

Purpose Metronomic chemotherapy (MCT) is an increasingly used treatment option in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced/metastatic breast cancer (MBC) after failure of endocrine-based therapies. Methods VinoMetro was a multicentre, open-label, single-arm, phase II study of metronomic oral vinorelbine (VRL; 30 mg/day) as a first-line chemotherapy (CT) in patients with HR+/HER2− MBC after endocrine failure. The primary endpoint was the clinical benefit rate (CBR) at 24 weeks. Results Between January 2017 and April 2019, nine patients were enrolled. The CBR was 22.2% (90% confidence interval [CI] 4.1–55.0), p = 0.211. The median progression-free survival (PFS) was 12.0 weeks (95% CI 11.3–12.7). Grade 3–4 adverse events (AEs) occurred in 22.2% of patients. One patient died of febrile neutropenia. Conclusion VinoMetro (AGO-B-046) was closed early after nine patients and occurrence of one grade 5 toxicity in agreement with the lead institutional review board (IRB). Metronomic dosing of oral VRL in HR+/HER2− MBC as first-line CT after failure of endocrine therapies showed only limited benefit in this population. Trial registration number and date of registration ClinicalTrials.gov Identifier: NCT03007992; December 15, 2016.

To assess missed opportunities for reducing fatal opioid overdoses, characteristics of decedents by opioid overdose with and without problematic opioid use who received health care services within one year of death were examined.Of 157 decedents in the Worcester, Massachusetts, area between 2008 and 2012, 112 had contact with the health care system. Electronic medical records were reviewed for clinical characteristics, health service use, universal precautions, and substance use disorder management. Problematic opioid use was defined as individuals having documented opioid use disorders or aberrant drug-related behavior. Data were analyzed with chi-square tests with adjusted residual for categorical variables and t tests for continuous variables.Decedents were predominantly Caucasian males with a mean±SD age of 41.0±11.7. Problematic opioid use by definition meant users (N=53) had opioid use disorder as a principal diagnosis and were likely to have a comorbid substance use disorder. Decedents with nonproblematic opioid use had diagnoses of chronic pain and mental illness. They were more likely to have been seen last in surgical and subspecialty settings (29% versus 11%). The proportion with an opioid prescription was higher among those with problematic use (72% versus 37%) who also had a higher total daily morphine equivalent, compared with those with nonproblematic use (165.4±282.7 versus 55.6±117.7 mg per day).Persons with problematic opioid use are a recognizable group with a high risk of death by opioid overdose whose therapeutic management needs improvement to reduce fatal outcomes. Different strategies must be developed for identifying and treating nonproblematic opioid use to reduce risk of death.

Am I Part of the Cure or Am I Part of the Disease? A front-line physician wonders how he can protect a vulnerable member of his household from the pathogens he’s exposed to in the ED — especially i...

Background Mucous membrane pemphigoid (MMP) is an autoimmune subepithelial blistering disease with predominant involvement of mucosal surfaces. It is usually diagnosed by direct immunofluorescence microscopy of frozen biopsies, demonstrating linear deposits of complement, IgG or IgA along the basement membrane. The aim of this study was to investigate the utility of immunohistochemistry on formalin-fixed, paraffin-embedded tissue biopsies for the diagnosis of MMP and to compare its sensitivity to that of direct immunofluorescence microscopy. Methods We examined 50 biopsies from 34 patients with immunologically confirmed MMP by immunohistochemistry for C3d, C4d, IgG and IgA. Results Linear deposits of C3d were detected in 46% of biopsies, and 53% of patients had at least one biopsy positive for C3d. Linear deposits of C4d were detected in 52% of biopsies and 59% of patients had at least one biopsy positive for C4d. Overall, 56% of biopsies and 68% of patients were positive by either C3d or C4d or both stainings. The sensitivity of either staining in mucosal biopsies was lower than in skin samples. Basement membrane deposits of IgG or IgA could not be detected in any biopsy. Conclusions Our findings demonstrate that immunohistochemistry for C3d or C4d is a helpful screening procedure for cases of suspected MMP where frozen tissue is not readily available. Negative findings, however, do not exclude a possible diagnosis of MMP and should prompt an additional biopsy for direct immunofluorescence studies. Immunohistochemical detection of IgG or IgA cannot yet be used for the diagnosis of MMP.

Nearly half of medical care in the United States is managed through the emergency department, a large portion of which could be managed by “lateral” health services provided by public health facilities like human immunodeficiency virus (HIV) prophylaxis, alcohol and drug treatment programs, emergency psychiatric resources, and medical respite or rehabilitation centers. These options may be underutilized due to lack of knowledge of their services and demographics by patients and health care workers alike. We aimed to educate all levels of emergency medicine trainees and staff to citywide services via bike tour. Participants reported an improved understanding of health services as well as a sense of “camaraderie” toward lateral health services and other providers on the rides.

The most prevalent etiologies of splenomegaly (SM) are easily detected in routine clinical practice. However, after these first-line diagnoses have been ruled out, many cases remain unexplained. Frequently, signs and symptoms are non-specific hiding rare etiologies such as Lysosomal Storage Diseases (LSD) (e.g., Gaucher disease (GD), Niemann-Pick disease type B). SplenoMegaly Study (SMS) aims to estimate the prevalence of different etiologies in unexplained SM and to describe their diagnostic work-up. We present here the final results of the study. SMS is a prospective, observational, multi-center, longitudinal study performed in France. All patients with unexplained SM, aged ≥15 years, consulting to the French hematology or internal medicine departments were invited to take part of the study. SM was confirmed by echography or CT-scan with a craniocaudal length ≥13 cm; unexplained was defined as negative clinical and biological routine workup. All conducted exams and tests for diagnosis purpose were under each physician's responsibility. For each patient, last visit took place when an etiology was identified or up to 12 months after inclusion. From Sept-2015 to Apr-2020, 505 patients were enrolled by 87 centers (secondary centers [71.3%] and tertiary centers [28.7%]). Physicians were mainly internists (52.9%) or hematologists (46.0%). Patients characteristics at inclusion were as follows: male gender, 61.2%; median age, 51.0 years old (16-94 years old); median spleen length, 15.0 cm (13-30 cm); heterogeneous spleen structure, 11.1%. A total of 501 patients completed the study. After a median duration of 6.6 months, 232 patients (46.3%) received a diagnosis. When compared to patients without diagnosis, patients with diagnosis were older (median age 59.5 vs 45.0; p In SMS, patients at inclusion had unexplained SM despite routine clinical and biologic analysis. The diagnostic yield improved after further medical evaluations reaching an etiologic diagnosis in 46% of patients. Patients with an established diagnosis were older, had a larger spleen and altered biological parameters compared to patients without diagnosis. Interestingly, non-malignant diseases accounted for 61.3% of diagnoses. It is noteworthy the diversity of LSD etiologies obtained: 10 patients (4%) were diagnosed with LSD, including 4 GD1 patients. This study provides useful new information to optimize the diagnostic strategy of splenomegaly poorly explained by routine workup. SMS is sponsored by Sanofi-Genzyme. Figure 1 Figure 1. Disclosures Denis: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Séné: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Costello: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Michaud: Sanofi: Honoraria, Research Funding. Hellé: Sanofi: Current Employment. Lagadec: Sanofi: Current Employment. Bauduer: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sanhes: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Urbanski: Sanofi: Honoraria, Research Funding. Berger: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

While important advances have been recently achieved in the optimization of lipid classes' separation, information on the specific determination of medium polarity lipids such as sphingolipids (SLs) in highly complex matrices remains fragmentary. In human, disorders of SL metabolism known as sphingolipidoses are a heterogeneous group of inherited disorders affecting primarily the central nervous. Early diagnosis of these conditions is of importance notably when a corrective therapy is available. The diagnosis is generally based on the determination of specific SLs in plasma and red blood cells (RBCs). For instance, glucosylceramide (GL1), glucosylsphingosine (Lyso-GL1), sphingosine (Sph), and sphingosine-1-phosphate (S1P) are proposed as relevant biomarkers for Gaucher disease (GD). Our main objective was to evaluate these biomarker candidates in a cohort of GD patients. However, most of current methods of GL1, Lyso-GL1, Sph, and S1P determination in plasma of GD patients require at least two liquid chromatographic runs. On the other hand, except for GL1 nothing is known concerning the RBC sphingolipid content. Yet, several reversed phase LC-MS methods of SLs separation and/or determination in various media with different sample preparation approaches have been proposed since 2010. Here we focused on stationary phase selection and mobile phase composition as well as on the sample preparation step to optimize and validate an UHPLC-MS/MS method for the simultaneous quantification of the four sphingolipids in both plasma and RBCs. A comparison between seven stationary phases including two RP18, two polar embedded RP18, and three HILIC phases shows that under our conditions polar embedded RP18 phases are the most appropriate for the separation of the four SLs, in terms of efficiency, peak symmetry, and separation time. In the same way, a comparison between a single step extraction with methanol and a liquid-liquid extraction with a mixture of methanol/methyl tert-butyl ether, shows that the latter mixture is the most appropriate for the extraction of SLs in terms of recovery and absence of matrix effect. After validation, this method was applied to the evaluation of the targeted SLs in a cohort of 15 known GD patients. The obtained results show that Lyso-GL1 is the only relevant biomarker in both plasma and RBCs for GD diagnosis. As the proposed method is applicable to the determination in such a highly complex matrices of four SLs with a large difference in polarity, and as the sample preparation procedure is freedom of matrix effects, this method can be easily adapted to a large diversity of samples.

BACKGROUND: Pyruvate kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells. METHODS: In this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase. RESULTS: Common adverse events, including headache and insomnia, occurred at the time of drug initiation and were transient; 92% of the episodes of headache and 47% of the episodes of insomnia resolved within 7 days. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). Hemoglobin responses were observed only in patients who had at least one missense PKLR mutation and were associated with the red-cell pyruvate kinase protein level at baseline. CONCLUSIONS: The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Adverse effects were mainly low-grade and transient. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916.).

Background Health systems in low- and middle-income countries face considerable challenges in providing high-quality accessible care. eHealth has had mounting interest as a possible solution given the unprecedented growth in mobile phone and internet technologies in these locations; however, few apps or software programs have, as of yet, gone beyond the testing phase, most downloads are never opened, and consistent use is extremely rare. This is believed to be due to a failure to engage and meet local stakeholder needs and the high costs of software development. Objective World Health Organization Basic Emergency Care course participants requested a mobile point-of-care adjunct to the primary course material. Our team undertook the task of developing this solution through a community-based participatory model in an effort to meet trainees’ reported needs and avoid some of the abovementioned failings. We aimed to use the well-described Lean software development strategy—given our familiarity with its elements and its ubiquitous use in medicine, global health, and software development—to complete this task efficiently and with maximal stakeholder involvement. Methods From September 2016 through January 2017, the Basic Emergency Care app was designed and developed at the University of California San Francisco. When a prototype was complete, it was piloted in Cape Town, South Africa and Dar es Salaam, Tanzania—World Health Organization Basic Emergency Care partner sites. Feedback from this pilot shaped continuous amendments to the app before subsequent user testing and study of the effect of use of the app on trainee retention of Basic Emergency Care course material. Results Our user-centered mobile app was developed with an iterative participatory approach with its first version available within 6 months and with high acceptance—95% of Basic Emergency Care Course participants felt that it was useful. Our solution had minimal direct costs and resulted in a robust infrastructure for subsequent assessment and maintenance and allows for efficient feedback and expansion. Conclusions We believe that utilizing Lean software development strategies may help global health advocates and researchers build eHealth solutions with a process that is familiar and with buy-in across stakeholders that is responsive, rapid to deploy, and sustainable.

Impaired cutaneous wound healing remains a major healthcare challenge. The enormity of this challenge is compounded by the lack of preclinical human skin wound healing models that recapitulate selected key factors underlying impaired healing, namely hypoxia/poor tissue perfusion, oxidative damage, defective innervation, and hyperglycaemia. Since organ-cultured human skin already represents a denervated and impaired perfusion state, we sought to further mimic “pathological” wound healing conditions by culturing experimentally wounded, healthy full-thickness frontotemporal skin from three healthy female subjects for three days in either serum-free supplemented Williams’ E medium or in unsupplemented medium under “pathological” conditions (i.e. hypoxia [5% O2], oxidative damage [10 mM H2O2], absence of insulin, excess glucose). Under these “pathological” conditions, dermal–epidermal split formation and dyskeratosis were prominent in organ-cultured human skin, and epidermal reepithelialisation was significantly impaired (p p p p p p p

Diet has a significant impact on human health, yet it is poorly represented or significantly oversimplified in most preclinical animal studies. A majority of animals used in preclinical studies are...

Diet and alcohol consumption are significant contributors to health and disease worldwide. Liver disease is a consequence of poor diet and alcohol consumption; however preclinical animal studies ha...

Diet remains a key contributor to health and disease worldwide. However, diet is routinely overlooked or oversimplified in basic biomedical research. Most preclinical animal studies are performed i...

Sepsis is a healthcare burden and has a mortality rate that exceeds many forms of cancer and AIDS combined. Previous research has shown obesity to exacerbate the severity of sepsis in both human an...

Patients with multiple myeloma are generally older and vary in fitness levels, which may influence the clinical benefit of treatment. Patients from the large, phase 3 FIRST trial in newly diagnosed multiple myeloma (NDMM) were retrospectively investigated to determine outcomes based on frailty using scores for age, Charlson Comorbidity Index (CCI), and Eastern Cooperative Oncology Group performance status (ECOG PS), instead of the EQ-5D quality-of-life questionnaire, as previously reported. ECOG PS (n = 1618) was investigated in frailty groups: frail (49%) and nonfrail (51%). Frail patients experienced worse progression-free and overall survival vs nonfrail patients. Prognostic assessment was improved when combining frailty and International Staging System stage (I/II vs III). Frail patients had a higher risk of developing grade 3/4 treatment-emergent adverse events. Treatment effects observed in the FIRST trial were confirmed per frailty group and per frailty and ISS group. The use of this ECOG PS–containing frailty scale as a predictive measure of clinical outcomes in patients with transplant-ineligible NDMM is supported by data from the FIRST trial. This score, based on age, CCI, and ECOG PS, can be easily replicated and may help design future myeloma studies in frail or nonfrail elderly patients., SCOPUS: ar.j, info:eu-repo/semantics/published

International audience; Gaucher disease is a rare inherited disease caused by a deficiency in glucocerebrosidase leading to lipid accumulation in cells of mononuclear-macrophage lineage known as Gaucher cells. Visceral enlargement, bone involvement, mild anemia and thrombocytopenia are the major manifestations of Gaucher disease. We have previously demonstrated that the red blood cells from patients exhibit abnormal properties, which indicates a new role in Gaucher disease pathophysiology. To investigate whether erythroid progenitors are affected, we examined the in vitro erythropoiesis from the peripheral CD34+ cells of patients and controls. CD34− cells were differentiated into macrophages and co-cultivated with erythroblasts. We showed an accelerated differentiation of erythroid progenitors without maturation arrest from patients compared to controls. This abnormal differentiation persisted in the patients when the same experiments were performed without macrophages, which strongly suggested that dyserythropoiesis in Gaucher disease is secondary to an inherent defect in the erythroid progenitors. The accelerated differentiation was associated with reduced cell proliferation. As a result, less mature erythroid cells were generated in vitro in the Gaucher disease cultures compared to the control. We then compared the biological characteristics of untreated patients according to their anemic status. Compared to the non-anemic group, the anemic patients exhibit higher plasma levels of growth differentiation factor-15, a marker of ineffective erythropoiesis, but they had no indicators of hemolysis and similar reticulocyte counts. Taken together, these results demonstrated an unsuspected dyserythropoiesis that was independent of the macrophages and could participate, at least in part, to the basis of anemia in Gaucher disease.

BACKGROUND Previous pilot studies have shown the feasibility of preoperative chemotherapy in patients with medulloblastoma, but benefits and risks compared with initial surgery have not been assessed. METHODS Two therapeutic strategies were retrospectively compared in 92 patients with metastatic medulloblastoma treated at Gustave Roussy, France, between 2002 and 2015: surgery at diagnosis (n=54; group A) and surgery delayed after carboplatin and etoposide-based preoperative therapy (n=38; group B). Treatment strategies were similar in both groups. RESULTS The rate of complete tumor excision was significantly higher in group B than in group A (93.3% versus 57.4%, p=0.0013). Post-operative complications, chemotherapy-associated side effects and local progressions were not increased in group B. Preoperative chemotherapy led to a decrease in the primary tumor size in all patients, 4/38 patients experiencing meanwhile a distant progression. The histological review of 19 matched tumor pairs (before and after chemotherapy) showed that proliferation was reduced and histological diagnosis feasible and accurate even after preoperative chemotherapy. The 5-year progression-free and overall survival rates were comparable between groups. Comparison of the longitudinal neuropsychological data showed that intellectual outcome tended to be better in group B (the mean predicted intellectual quotient value was 6 points higher throughout the follow-up). CONCLUSION Preoperative chemotherapy is a safe and efficient strategy for metastatic medulloblastoma. It increases the rate of complete tumor excision and may improve the neuropsychological outcome without jeopardizing survival.

International audience; Erythropoiesis-stimulating agents are generally the first line of treatment of anemia in patients with lower-risk myelodysplastic syndrome. We prospectively investigated the predictive value of somatic mutations, and biomarkers of ineffective erythropoiesis including the flow cytometry RED score, serum growth-differentiation factor-15, and hepcidin levels. Inclusion criteria were no prior treatment with erythropoiesis-stimulating agents, low- or intermediate-1-risk myelodysplastic syndrome according to the International Prognostic Scoring System, and a hemoglobin level 4 (P=0.05) and a hepcidin:ferritin ratio 2000 pg/mL and a hepcidin:ferritin ratio

International audience; We describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a KCNN4 mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a PIEZO1 mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. PIEZO1-hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In KCNN4-related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a ‘Gardos channelopathy’. These data on the largest series to date indicate that PIEZO1-hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of PIEZO1-hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up.

Intravenous imiglucerase enzyme replacement therapy for Gaucher disease type 1 administered every 2 weeks is at variance with the imiglucerase plasma half-life of a few minutes. We hypothesized that studying the pharmacokinetics of imiglucerase in blood Gaucher disease type 1 monocytes would be more relevant for understanding enzyme replacement therapy responses. Glucocerebrosidase intra-monocyte activity was studied by flow cytometry. The pharmacokinetics of imiglucerase was analyzed using a population-pharmacokinetic model from a cohort of 31 patients with Gaucher disease type 1 who either started or were receiving long-term treatment with imiglucerase. A pharmacokinetic analysis of imiglucerase showed a two-compartment model with a high peak followed by a two-phase exponential decay (fast phase half-life: 0.36 days; slow phase half-life: 9.7 days) leading to a median 1.4-fold increase in glucocerebrosidase intra-monocyte activity from the pre-treatment activity (p = 0.04). In patients receiving long-term treatment, for whom the imiglucerase dose per infusion was chosen on the basis of disease aggressiveness/response, imiglucerase clearance correlated with the administered dose. However, the residual glucocerebrosidase intra-monocyte activity value was dose independent, suggesting that the maintenance of imiglucerase residual activity is patient specific. Endogenous pre-treatment glucocerebrosidase intra-monocyte activity was the most informative single parameter for distinguishing patients without (n = 10) and with a clinical indication (n = 17) for starting enzyme replacement therapy (area under the receiver operating characteristic curve: 0.912; 95% confidence interval 0.8–1; p

Objectives To assess the reduction of transfusions rate in transfusion-dependent patients with low-risk myelodysplastic syndrome (MDS) with iron overload treated with deferasirox. Methods Prospective observational study. Primary endpoint was reduction in transfusion requirements (RTR) at 3 months, (assessed on 8-week period). Secondary endpoints were hematologic improvement according to International Working Group (IWG) 2006 criteria at 3, 6, and 12 months. Results Fifty-seven patients were evaluable. After 3 months of chelation, no effect was seen on transfusion requirement (5.9 packed red blood cells (PRBC) vs 5.8 before chelation). According to the Kaplan-Meier analysis, the probability of RTR at 3, 6, and 12 months was assessed as 3.5%, 9.1%, and 18.7%, respectively. Median duration of RTR was 182 days. However, during the 12-month follow-up after deferasirox initiation, 17 patients (31.5%) achieved minor erythroid response [HI-E] according to IWG criteria, 10 of whom having achieved Hb improvement at month 12. Conclusion After 3 months of treatment, deferasirox had no impact on transfusion requirement in regularly transfused patients with low-risk MDS. However, deferasirox could induce 31% of erythroid response during the 12-month follow-up period thus suggesting that iron chelation therapy with deferasirox may induce an effect on hematopoiesis in a subset of patients with MDS and iron overload.

Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug's effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin β. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34(+)CD38(-) hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD34(+)CD38(-) cell-derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. This trial was registered at www.clinicaltrials.gov as #NCT01718379.

International audience; Objective. We describe myelodysplastic syndrome (MDS)–associated systemic inflammatory and autoimmune diseases (SIADs), their treatments and outcomes and the impact of SIADs on overall survival in a French multicentre retrospective study. Methods. In this study, 123 patients with MDS and SIADs were analysed. Results. Mean age was 70 years (s.d. 13) and the male:female ratio was 2. The SIADs were systemic vasculitis in 39 (32%) cases, CTD in 31 (25%) cases, inflammatory arthritis in 28 (23%) cases, a neutrophilic disorder in 12 (10%) cases and unclassified in 13 cases (11%). The SIADs fulfilled the usual classification criteria in 75 (66%) cases, while complete criteria were not reached in 21 (19%) cases. A significant association was shown between chronic myelomonocytic leukaemia (CMML) and systemic vasculitis (P = 0.0024). One hundred and eighteen (96%) SIAD patients were treated (91% with steroids), with an 83% response to first-line treatment, including 80% for steroids alone. A second-line treatment for SIADs was required for steroid dependence or relapse in 48% of cases. The effect of MDS treatment on SIADs could be assessed in 11 patients treated with azacytidine and SIAD response was achieved in 9/11 (80%) and 6/11 (55%) patients at 3 and 6 months, respectively. Compared with 665 MDS/CMML patients without SIADs, MDS/CMML patients with SIADs were younger (P \textless 0.01), male (P = 0.03), less often had refractory anaemia with ring sideroblasts (P \textless 0.01), more often had a poor karyotype (16% vs 11%, P = 0.04) and less frequently belonged to low and intermediate-1 International Prognostic Scoring System categories, but no survival difference was seen between patients with MDS-associated SIADs and without SIADs (P = 0.5). Conclusion. The spectrum of SIADs associated to MDS is heterogeneous, steroid sensitive, but often steroid dependent

INTRODUCTION: Erythropoiesis stimulating agents (ESA) are generally the first line of treatment of anaemia in lower risk myelodysplastic syndrome (MDS) patients. We prospectively investigated the predictive value of somatic mutations, and biomarkers of ineffective erythropoiesis including flow cytometry RED score, serum GDF-15, and hepcidin levels. METHODS: Inclusion criteria were: ESA naive, IPSS low or intermediate-1 MDS with Hemoglobin (Hb) level< 10g/dL. Patients received epoetin zeta 40 000 IU/week and erythroid response (HI-E, IWG 2006 criteria) was assessed at W12. sEPO level, iron parameters and hepcidin, flow cytometry (FC) Ogata and Red Score (RS), GDF-15, and molecular analysis by NGS were determined at baseline. RESULTS: 70 patients were included. Median age was 78 years. There were 22 RCMD, 19 RCUD, 14 RARS, 4 RAEB-1, 6 CMML, 2 del 5q-, 3 unclassifiable, R-IPSS was 13 very low, 47 low, 9 intermediate and high. Twenty patients were transfusion-dependent. HI-E was 48% and median duration of response was 26 months. At baseline, non-responders had significantly higher FC Red Score, lower hepcidin/ferritin ratio, lower IPSS. In multivariate analysis, only RS>4 at T0 (p=0.05) and hepcidin/ferritin 2000 pg/ml and hepcidin/ferritin

International audience; Giant congenital melanocytic nevi may be symptomatically isolated, or syndromic. Associations with capillary malformations are exceptional, and development of epidermal cysts has not been described. A 71-year old patient with a giant congenital melanocytic nevus of the lower back, buttocks and thighs was asymptomatic except for unexpected hemorrhage during partial surgical excision years before. Blunt trauma at age 64 initiated recurrent, severe pain under the nevus; multiple large epidermal cysts developed within it. Imaging and biopsy showed a large, non-pulsatile venous malformation intermingled with the deep nevus. A low-abundance, heterozygous BRAF c.1799T>A (p.V600E) mutation was present in both the gluteal and occipital “satellite” nevi; additional mutations in NRAS, GNAQ, GNA11, HRAS and PIK3CA were undetectable. This is the first demonstration of an identical BRAF mutation in multiple congenital nevi from the same individual, confirming genetic heterogeneity in giant nevi. This exceptional case indicates that constitutive activation of BRAF can be an underlying cause of unusual associations of giant nevi with vascular malformations, and that the latter may be included among the somatic RASopathies.

Introduction A comprehensive geriatric assessment (CGA) evaluating several domains of health is recommended for elderly patients with cancer. Effects of altered domains on the risk of death in this population need to be clarified. The aim of this study was to estimate the independent association of each CGA domain to overall survival (OS). Method Patients included in the ONCODAGE cohort completed a CGA at baseline. Cox models (one per domain) estimated the hazard ratio (HR) of death for each CGA domain. Directed Acyclic Graphs (DAGs) selected specific sets of adjustment factors for each model. Results The analysis included 1264 patients (mean age: 78 years, women: 70%). Median follow-up was 5.2 years, and 446 patients died. Each altered domain had a detrimental effect on survival, sometimes dependent on gender, age, education or time from inclusion. Nutritional status had a time-varying effect, with higher mortality rates if altered only within the first 3 years of follow-up. In case of altered mobility, the risk of death was higher only for the youngest patients and, in case of altered autonomy, only for the youngest women. An altered neurological state led to higher mortality rates; this effect increased with the level of education. Patients with altered psychological status or more than four comorbidities at baseline had also higher mortality rates. Conclusions Patients with an altered CGA domain have a higher risk of death than those without any alteration. The effect of some alterations is different in some subgroups or at a given time of the treatments.

International audience

The risk and clinical significance of cardiac iron overload due to chronic transfusion varies with the underlying disease. Cardiac iron overload shortens the life expectancy of patients with thalassemia, whereas its effect is unclear in those with myelodysplastic syndromes (MDS). In patients with sickle cell anemia (SCA), iron does not seem to deposit quickly in the heart. Our primary objective was to assess through a multicentric study the prevalence of cardiac iron overload, defined as a cardiovascular magnetic resonance T2*8 ECs in the past year, and age older than 6 years. We included from 9 centers 20 patients with thalassemia, 41 with SCA, and 25 with MDS in 2012-2014. Erythrocytapharesis did not consistently prevent iron overload in patients with SCA. Cardiac iron overload was found in 3 (15%) patients with thalassemia, none with SCA, and 4 (16%) with MDS. The liver iron content (LIC) ranged from 10.4 to 15.2 mg/g dry weight, with no significant differences across groups (P = 0.29). Abnormal T2* was not significantly associated with any of the measures of transfusion or chelation. Ferritin levels showed a strong association with LIC. Non-transferrin-bound iron was high in the thalassemia and MDS groups but low in the SCA group (P