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Purpose: This study examined adherence with a physical activity tracker and patterns of activity among different subgroups of African American/Black breast cancer survivors (AABCS). Design: Secondary analysis of weight loss trial that used an activity tracker (FitBit) with or without a commercial eHealth program (SparkPeople) over 12 months. Setting and Subjects: AABCS (N = 44) in New Jersey. Measures and Analysis: Adherence with tracker use, steps per day, and active minutes per week were compared by demographic and clinical characteristics using nonparametric statistics. Results: Median adherence was over 6 days per week throughout the 12-months. Adherence was significantly correlated with steps and active minutes (p < 0.015). Groups with lower adherence included: those with 5 or more conditions (p = 0.039), had higher number of household members (p = 0.008), and younger than 60 years (p = 0.044). Median number of steps per day remained consistently around 7000 throughout 12 months. Factors associated with lower activity included: age > 60; retirement; higher number of household members, comorbidity, or baseline BMI; and those in the SparkPeople + Fitbit group. Self-monitoring, goal setting, and self-efficacy were significantly correlated with activity levels (p < 0.05). Conclusion: Use of a physical activity tracker may help increase activity levels in AABCS. Certain subgroups, e.g. those older than age 60 years, retired, with BMI over 40, higher number of comorbidities or more household members, may require additional interventions.

Patients with Myelodysplastic syndromes (MDS) have few therapy options for sustainable responses in the frontline setting, and even less after hypomethylating agent (HMA) failure in relapsed and refractory setting. The only potential cure is an allogeneic hematopoietic stem cell transplant which is an unrealistic option for the majority of MDS patients. Immunotherapy with checkpoint inhibition, CAR-T cells, and vaccine therapy few have shown promise in a variety cancer and have now been tested in patients with MDS. Most trials have focused on AML patients and included small numbers of MDS patients. Until now, a dedicated review of immunotherapy outcomes in MDS patients has been lacking. Thus, herein we review outcomes of MDS patients after immunotherapies on a variety of clinical trials reported to date.

Background Single patient Investigational New Drug (IND) applications are one mechanism through which experimental therapies are accessed for children with cancer. The landscape of use, outcomes, and toxicity from single patient INDs remains unknown in pediatric oncology. Methods We performed a retrospective analysis of all single patient INDs requested and prescribed at a single institution between 1/1/2007 and 5/1/2019. We report aggregate data from the US Food and Drug Administration (FDA) on single patient IND applications over the final two years of the study (2017–2019). We report an overview of all IND applications, as well as clinical descriptions of patients, treatments, outcomes, and toxicity. Results Over the 2‐year period, the FDA approved all 171 submitted single patient IND requests for pediatric oncology. We identified 56 requests from our center during the 12‐year study period, and all were approved (median time from FDA submission to approval: 1 day (range 0–12)). 71% of requests were based on disease histology. Lack of pediatric clinical trial (65%) was the most common reason for use. 48 approved requests were ultimately administered. The median duration of treatment was 84 days (range: 4–1590), with 3 patients remaining on treatment at time of analysis. Only 7% discontinued treatment due to toxicity. Three‐year overall survival was 50% (95% CI, 35–64). Conclusions Single patient INDs in pediatric oncology were universally approved in our national and single‐center analysis. In our cohort, single patient INDs were primarily utilized based on disease histology, rather than genomics, for agents that lacked a clinical trial., Single patient Investigational New Drug (IND) applications in pediatric oncology are universally approved in a timely fashion in our analysis. Single patient IND therapy is pursued for a range of reasons, with few patients discontinuing therapy due to toxicity.

Background Successful trauma resuscitation relies on multi-disciplinary collaboration. In most academic programs, general surgery (GS) and emergency medicine (EM) residents rarely train together before functioning as a team. Methods In our Multi-Disciplinary Trauma Evaluation and Management Simulation (MD-TEAMS), EM and GS residents completed manikin-based trauma scenarios and were evaluated on resuscitation and communication skills. Residents were surveyed on confidence surrounding training objectives. Results Residents showed improved confidence running trauma scenarios in multi-disciplinary teams. Residents received lower communication scores from same-discipline vs cross-discipline faculty. EM residents scored higher in evaluation and planning domains; GS residents scored higher in action processes; groups scored equally in team management. Strong correlation existed between team leader communication and resuscitative skill completion. Conclusion MD-TEAMS demonstrated correlation between communication and resuscitation checklist item completion and communication differences by resident specialty. In the future, we plan to evaluate training-related resident behavior changes and specialty-specific communication differences by residents.

In Dec 2019, pneumonia cluster in China caused by a previously unknown virus, now called Novel Coronavirus 2019, occurred, causing respiratory as well as gastrointestinal symptoms. The respiratory symptoms usually include common cold; pneumonia causing generally mild disease. There are, however, several examples of severe disease-causing coronaviruses that include severe acute respiratory syndrome (SARS)-Cov first identified in China in 2003; and Middle East Respiratory Syndrome (MERS) Cov, first identified in Saudi Arabia in 2012. In 2019 the n-COV was first detected in China. At present, there are many cases in China and along with it, this has spread to other countries as well. The article aims at giving general information about the novel coronavirus and its impact on vaccine preventable diseases. Currently, there is a big outbreak in India and other countries as well. By ensuring early immunisation, protecting people and groups of persons, reducing the susceptibility of a vaccine preventable disease (VPD) outbreak not only saves lives but also requires less resources and helps to reduce the health care burden. Immunizations are important resources for health care that protect people vulnerable to VPD. Countries may therefore contribute to the maintenance of immunisation programmes by using methods that adopt the do-no-harm principle and limit the transmission of COVID-19 when conducting immunisation activities.

Healthcare facilities are vulnerable to SARS-CoV-2 introductions and subsequent nosocomial outbreaks. Antigen rapid diagnostic testing (Ag-RDT) is widely used for population screening, but its health and economic benefits as a reactive response to local surges in outbreak risk are unclear. We simulate SARS-CoV-2 transmission in a long-term care hospital with varying COVID-19 containment measures in place (social distancing, face masks, vaccination). Across scenarios, nosocomial incidence is reduced by up to 40-47% (range of means) with routine symptomatic RT-PCR testing, 59-63% with the addition of a timely round of Ag-RDT screening, and 69-75% with well-timed two-round screening. For the latter, a delay of 4-5 days between the two screening rounds is optimal for transmission prevention. Screening efficacy varies depending on test sensitivity, test type, subpopulations targeted, and community incidence. Efficiency, however, varies primarily depending on underlying outbreak risk, with health-economic benefits scaling by orders of magnitude depending on the COVID-19 containment measures in place., Healthcare facilities are vulnerable to SARS-CoV-2 introductions and subsequent nosocomial outbreaks. Here, the authors simulate transmission in a long-term care facility with varying containment measures in place and evaluate reactive response with antigen rapid diagnostic testing.

Key Points CIBMTR prognostic score predicts PFS and OS of patients with DLBCL receiving axicabtagene ciloleucel treatment after a prior autoHCT failure.CIBMTR high/very high-risk score marks an adverse risk cohort where novel immunotherapy or relapse prevention approaches are warranted., Visual Abstract, Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR)-T cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto)HCT. Although the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis, we report outcomes of patients with DLBCL (≥18 years) undergoing a reduced intensity alloHCT or CAR-T therapy with axicabtagene ciloleucel during 2012 to 2019 after a prior auto-HCT failure and apply the CIBMTR prognostic model to CAR-T recipients. A total of 584 patients were included. The 1-year relapse, nonrelapse mortality, overall survival (OS), and progression-free survival for CAR-T treatment after autoHCT failure were 39.5%, 4.8%, 73.4%, and 55.7%, respectively. The corresponding rates in the alloHCT cohort were 26.2%, 20.0%, 65.6%, and 53.8%, respectively. The 1-year OS of alloHCT recipients classified as low-, intermediate- and high/very high-risk groups according to the CIBMTR prognostic score was 73.3%, 59.9%, and 46.3%, respectively (P = .002). The corresponding rates for low-, intermediate-, and high/very high-risk CAR-T patients were 88.4%, 76.4%, and 52.8%, respectively (P < .001). This registry analysis shows that both CAR-T and alloHCT can provide durable remissions in a subset of patients with DLBCL relapsing after a prior autoHCT. The simple CIBMTR prognostic score can be used to identify patients at high risk of treatment failure after either procedure. Evaluation of novel relapse mitigations strategies after cellular immunotherapies are warranted in these high-risk patients.

BACKGROUND: Patients with diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M mutation as a shared neoantigen in HLA-A*02.01(+), H3.3K27M(+) DMGs. Within the Pacific Pediatric Neuro-Oncology Consortium, we assessed the safety and efficacy of an H3.3K27M-targeted peptide vaccine. METHODS: Newly diagnosed patients, aged 3–21 years, with HLA-A*02.01(+) and H3.3K27M(+) status were enrolled in stratum A (DIPG) or stratum B (nonpontine DMG). Vaccine was administered in combination with polyinosinic-polycytidylic acid-poly-I-lysine carboxymethylcellulose (poly-ICLC) every 3 weeks for 8 cycles, followed by once every 6 weeks. Immunomonitoring and imaging were performed every 3 months. Imaging was centrally reviewed. Immunological responses were assessed in PBMCs using mass cytometry. RESULTS: A total of 19 patients were enrolled in stratum A (median age,11 years) and 10 in stratum B (median age, 13 years). There were no grade-4 treatment-related adverse events (TRAEs). Injection site reaction was the most commonly reported TRAE. Overall survival (OS) at 12 months was 40% (95% CI, 22%–73%) for patients in stratum A and 39% (95% CI, 16%–93%) for patients in stratum B. The median OS was 16.1 months for patients who had an expansion of H3.3K27M-reactive CD8(+) T cells compared with 9.8 months for their counterparts (P = 0.05). Patients with DIPG with below-median baseline levels of myeloid-derived suppressor cells had prolonged OS compared with their counterparts (P < 0.01). Immediate pretreatment dexamethasone administration was inversely associated with H3.3K27M-reactive CD8(+) T cell responses. CONCLUSION: Administration of the H3.3K27M-specific vaccine was well tolerated. Patients with H3.3K27M-specific CD8(+) immunological responses demonstrated prolonged OS compared with nonresponders. TRIAL REGISTRATION: ClinicalTrials.gov NCT02960230. FUNDING: The V Foundation, the Pacific Pediatric Neuro-Oncology Consortium Foundation, the Pediatric Brain Tumor Foundation, the Mithil Prasad Foundation, the MCJ Amelior Foundation, the Anne and Jason Farber Foundation, Will Power Research Fund Inc., the Isabella Kerr Molina Foundation, the Parker Institute for Cancer Immunotherapy, and the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R35NS105068).

INTRODUCTION AND OBJECTIVE:This study seeks to compare perioperative outcomes between single port (SP) and multiport (MP) robot-assisted laparoscopic radical prostatectomy (RALP) cases utilizing pr...

The COVID-19 epidemic has forced most countries to impose contact-limiting restrictions at workplaces, universities, schools, and more broadly in our societies. Yet, the effectiveness of these unprecedented interventions in containing the virus spread remain largely unquantified. Here, we develop a simulation study to analyze COVID-19 outbreaks on three real-life contact networks stemming from a workplace, a primary school and a high school in France. Our study provides a fine-grained analysis of the impact of contact-limiting strategies at workplaces, schools and high schools, including: (1) Rotating strategies, in which workers are evenly split into two shifts that alternate on a daily or weekly basis; and (2) On-Off strategies, where the whole group alternates periods of normal work interactions with complete telecommuting. We model epidemics spread in these different setups using a stochastic discrete-time agent-based transmission model that includes the coronavirus most salient features: super-spreaders, infectious asymptomatic individuals, and pre-symptomatic infectious periods. Our study yields clear results: the ranking of the strategies, based on their ability to mitigate epidemic propagation in the network from a first index case, is the same for all network topologies (workplace, primary school and high school). Namely, from best to worst: Rotating week-by-week, Rotating day-by-day, On-Off week-by-week, and On-Off day-by-day. Moreover, our results show that below a certain threshold for the original local reproduction number R0local within the network (< 1.52 for primary schools, < 1.30 for the workplace, < 1.38 for the high school, and < 1.55 for the random graph), all four strategies efficiently control outbreak by decreasing effective local reproduction number to R0local < 1. These results can provide guidance for public health decisions related to telecommuting., Author summary The COVID-19 epidemics has forced most countries to impose prolonged contact-limiting restrictions at workplaces, universities, schools. Using simulation and taking into account the most salient epidemiological features of SARS-CoV-2, we analyze the risk of outbreak and the impact of contact-limiting strategies on three real-life contact networks stemming from a workplace, a primary school and a high school. The strategies investigated involve (1) Rotation, in which workers are evenly split into two shifts that alternate on a daily or weekly basis; and (2) On-Off, where the whole group alternates periods of normal work interactions with complete telecommuting. Our study yields clear results, whatever the studied network (workplace, primary school and high school), we find that, from best to worst: Rotating week-by-week, Rotating day-by-day, On-Off week-by-week, and On-Off day-by-day can all help mitigate transmission below a certain epidemicity threshold. In the current context where institutions and companies have to quickly take local organizational decisions and review their planning or agendas, our results should help inform public health decisions.

Animal models support a role for the gut microbiota in the development of hypertension. There has been a lack of epidemiological cohort studies to confirm these findings in human populations. We examined cross-sectional associations between measures of gut microbial diversity and taxonomic composition and blood pressure (BP) in 529 participants of the biracial (black and white) CARDIA study (Coronary Artery Risk Development in Young Adults). We sequenced V3-V4 regions of the 16S ribosomal RNA marker gene using DNA extracted from stool samples collected at CARDIA’s Year 30 follow-up examination (2015–2016; aged 48–60 years). We quantified associations between BP (hypertension [defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg or antihypertension medication use] and systolic BP) and within and between-person diversity measures. We conducted genera-specific multivariable-adjusted regression analysis, accounting for multiple comparisons using the false discovery rate. Hypertension and systolic BP were inversely associated with measures of α-diversity, including richness and the Shannon Diversity Index, and were distinguished with respect to principal coordinates based on a similarity matrix of genera abundance. Several specific genera were significantly associated with hypertension and systolic BP, though results were attenuated with adjustment for body mass index. Our findings support associations between within-person and between-person gut microbial community diversity and taxonomic composition and BP in a diverse population-based cohort of middle-aged adults. Future study is needed to define functional pathways that underlie observed associations and identify specific microbial targets for intervention.

Refractory and relapsed acute myeloid leukemia (AML) and T-lineage leukemia have poor prognosis and limited therapeutic options. Adoptive cellular immunotherapies are emerging as an effective treatment for patients with chemotherapy refractory hematological malignancies. Indeed, the use of unselected donor lymphocyte infusions has demonstrated successes in treating patients with AML and T-lineage leukemia post-allogeneic transplantation. The development of ex vivo manipulation techniques such as genetic modification or selection and expansion of individual cellular components has permitted the clinical translation of a wide range of promising cellular therapies for AML and T-cell acute lymphoblastic leukemia. Here, we will review clinical studies to date using adoptive cell therapy approaches and outline the major challenges limiting the development of safe and effective cell therapies for both types of acute leukemia.

BackgroundSurvivors of pediatric brain tumors are at risk for impaired development in multiple neuropsychological domains. The purpose of this study was to compare neuropsychological outcomes of pediatric brain tumor patients who underwent X-ray radiotherapy (XRT) versus proton radiotherapy (PRT).MethodsPediatric patients who underwent either XRT or PRT and received posttreatment age-appropriate neuropsychological evaluation—including measures of intelligence (IQ), attention, memory, visuographic skills, academic skills, and parent-reported adaptive functioning—were identified. Multivariate analyses were performed to assess differences in neuropsychological outcomes and included tests for interaction between treatment cohort and follow-up time.ResultsBetween 1998 and 2017, 125 patients with tumors located in the supratentorial (17.6%), midline (28.8%), or posterior fossa (53.6%) compartments received radiation and had posttreatment neuropsychological evaluation. Median age at treatment was 7.4 years. The PRT patient cohort had higher estimated SES and shorter median time from radiotherapy completion to last neuropsychological evaluation (6.7 vs 2.6 y, P < 0.001). On multivariable analysis, PRT was associated with higher full-scale IQ (β = 10.6, P = 0.048) and processing speed (β = 14.4, P = 0.007) relative to XRT, with trend toward higher verbal IQ (β = 9.9, P = 0.06) and general adaptive functioning (β = 11.4, P = 0.07). Planned sensitivity analyses truncating follow-up interval in the XRT cohort re-demonstrated higher verbal IQ (P = 0.01) and IQ (P = 0.04) following PRT, with trend toward improved processing speed (P = 0.09).ConclusionsPRT is associated with favorable outcomes for intelligence and processing speed. Combined with other strategies for treatment de-intensification, PRT may further reduce neuropsychological morbidity of brain tumor treatment.

Background Gene-mediated cytotoxic immunotherapy (GMCI) is a tumor-specific immune stimulatory strategy implemented through local delivery of aglatimagene besadenovec (AdV-tk) followed by anti-herpetic prodrug. GMCI induces T-cell dependent tumor immunity and synergizes with radiotherapy. Clinical trials in adult malignant gliomas demonstrated safety and potential efficacy. This is the first trial of GMCI in pediatric brain tumors. Methods This phase I dose escalation study was conducted to evaluate GMCI in patients 3 years of age or older with malignant glioma or recurrent ependymoma. AdV-tk at doses of 1 × 1011 and 3 × 1011 vector particles (vp) was injected into the tumor bed at the time of surgery followed by 14 days of valacyclovir. Radiation started within 8 days of surgery, and if indicated, chemotherapy began after completion of valacyclovir. Results Eight patients (6 glioblastoma, 1 anaplastic astrocytoma, 1 recurrent ependymoma) were enrolled and completed therapy: 3 on dose level 1 and 5 on dose level 2. Median age was 12.5 years (range 7-17) and Lansky/Karnofsky performance scores were 60-100. Five patients had multifocal/extensive tumors that could not be resected completely and 3 had gross total resection. There were no dose-limiting toxicities. The most common possibly GMCI-related adverse events included Common Terminology Criteria for Adverse Events grade 1-2 fever, fatigue, and nausea/vomiting. Three patients, in dose level 2, lived more than 24 months, with 2 alive without progression 37.3 and 47.7 months after AdV-tk injection. Conclusions GMCI can be safely combined with radiation therapy with or without temozolomide in pediatric patients with brain tumors and the present results strongly support further investigation. Clinical trial registry ClinicalTrials.gov NCT00634231.

BackgroundCirculation of non-SARS-CoV-2 respiratory viruses during the COVID-19 pandemic may alter quality of COVID-19 surveillance, with possible consequences for real-time analysis and delay in implementation of control measures. Here, we assess the impact of an increased circulation of other respiratory viruses on the monitoring of positivity rates of SARS-CoV-2 and interpretation of surveillance data.MethodsUsing a multi-pathogen Susceptible-Exposed-Infectious-Recovered (SEIR) transmission model formalizing co-circulation of SARS-CoV-2 and another respiratory we assess how an outbreak of secondary virus may inflate the number of SARS-CoV-2 tests and affect the interpretation of COVID-19 surveillance data. Using simulation, we assess to what extent the use of multiplex PCR tests on a subsample of symptomatic individuals can support correction of the observed SARS-CoV-2 percent positive during other virus outbreaks and improve surveillance quality.ResultsModel simulations demonstrated that a non-SARS-CoV-2 epidemic creates an artificial decrease in the observed percent positivity of SARS-CoV-2, with stronger effect during the growth phase, until the peak is reached. We estimate that performing one multiplex test for every 1,000 COVID-19 tests on symptomatic individuals could be sufficient to maintain surveillance of other respiratory viruses in the population and correct the observed SARS-CoV-2 percent positive.ConclusionsThis study highlights that co-circulating respiratory viruses can disrupt SARS-CoV-2 surveillance. Correction of the positivity rate can be achieved by using multiplex PCR, and a low number of samples is sufficient to avoid bias in SARS-CoV-2 surveillance.SummaryCOVID-19 surveillance indicators may be impacted by increased co-circulation of other respiratory viruses delaying control measure implementation. Continued surveillance through multiplex PCR testing in a subsample of the symptomatic population may play a role in fixing this problem.

Fistula formation between the kidney and the colon is a rare occurrence. Colorenal fistulas have been reported after renal cryoablation, calculous pyonephrosis, and renal cell carcinoma. Fistula formation is reported in as many as 35% of patients with Crohn's disease. Crohn's-related urinary fistulas may include enterovesical, enteroureteral, rectourethral, urethrocutaneous, and entero-urachal fistulas. Here, we report a rare case of a patient who was found to have a left colorenal fistula in the setting of a left staghorn calculus and recurrent urinary tract infections with a question about the eventual definitive management of the patient.

PURPOSE Patients with relapsed lymphomas often fail salvage therapies including high-dose chemotherapy and mono-antigen–specific T-cell therapies, highlighting the need for nontoxic, novel treatments. To that end, we clinically tested an autologous T-cell product that targets multiple tumor-associated antigens (TAAs) expressed by lymphomas with the intent of treating disease and preventing immune escape. PATIENTS AND METHODS We expanded polyclonal T cells reactive to five TAAs: PRAME, SSX2, MAGEA4, SURVIVIN, and NY-ESO-1. Products were administered to 32 patients with Hodgkin lymphomas (n = 14) or non-Hodgkin lymphomas (n = 18) in a two-part phase I clinical trial, where the objective of the first phase was to establish the safety of targeting all five TAAs (fixed dose, 0.5 × 107 cells/m2) simultaneously and the second stage was to establish the maximum tolerated dose. Patients had received a median of three prior lines of therapy and either were at high risk for relapse (adjuvant arm, n = 17) or had chemorefractory disease (n = 15) at enrollment. RESULTS Infusions were safe with no dose-limiting toxicities observed in either the antigen- or dose-escalation phases. Although the maximum tolerated dose was not reached, the maximum tested dose at which efficacy was observed (two infusions, 2 × 107 cells/m2) was determined as the recommended phase II dose. Of the patients with chemorefractory lymphomas, two (of seven) with Hodgkin lymphomas and four (of eight) with non-Hodgkin lymphomas achieved durable complete remissions (> 3 years). CONCLUSION T cells targeting five TAAs and administered at doses of up to two infusions of 2 × 107 cells/m2 are well-tolerated by patients with lymphoma both as adjuvant and to treat chemorefractory lymphoma. Preliminary indicators of antilymphoma activity were seen in the chemorefractory cohort across both antigen- and dose-escalation phases.

Background Many countries implemented national lockdowns to contain the rapid spread of SARS-CoV-2 and avoid overburdening healthcare capacity. Aim We aimed to quantify how the French lockdown impacted population mixing, contact patterns and behaviours. Methods We conducted an online survey using convenience sampling and collected information from participants aged 18 years and older between 10 April and 28 April 2020. Result Among the 42,036 survey participants, 72% normally worked outside their home, and of these, 68% changed to telework during lockdown and 17% reported being unemployed during lockdown. A decrease in public transport use was reported from 37% to 2%. Participants reported increased frequency of hand washing and changes in greeting behaviour. Wearing masks in public was generally limited. A total of 138,934 contacts were reported, with an average of 3.3 contacts per individual per day; 1.7 in the participants aged 65 years and older compared with 3.6 for younger age groups. This represented a 70% reduction compared with previous surveys, consistent with SARS-CoV2 transmission reduction measured during the lockdown. For those who maintained a professional activity outside home, the frequency of contacts at work dropped by 79%. Conclusion The lockdown affected the population's behaviour, work, risk perception and contact patterns. The frequency and heterogeneity of contacts, both of which are critical factors in determining how viruses spread, were affected. Such surveys are essential to evaluate the impact of lockdowns more accurately and anticipate epidemic dynamics in these conditions.

Antibiotic stewardship requires clear insight into antibiotic overuse and the syndromes that lead to prescription. The aim of this study was to estimate the proportion of antibiotic prescriptions attributable to acute lower respiratory tract infections (LRTIs) during the cold season. Using individual data from the French National Health Insurance (NHI) database, weekly time series were constructed of outpatient antibiotic (beta-lactams and macrolides) prescriptions between January 2010 and December 2017. Time series were also constructed of tenth edition of the International Classification of Diseases (ICD-10) discharge diagnoses from a national network of emergency departments (EDs), stratified by specific syndromes (pneumonia, bronchitis, bronchiolitis and influenza-like illness). The number of outpatient antibiotic prescriptions attributable to these syndromes during the cold season in France was modeled and estimated for the entire population, young children (≤5 years) and the elderly (≥75 years). LRTIs accounted for 40% (95% confidence interval [95% CI]: 29, 52) of outpatient antibiotic use during the cold season for the entire population, including 23% (95% CI: 13, 33) and 17% (95% CI: 13, 22) for bacterial and viral infections, respectively. In children and the elderly, viral LRTIs were the reason for 38% (95% CI: 31, 46) and 20% (95% CI: 16, 25) of outpatient antibiotic use, respectively (with bronchiolitis accountable for half of use in young children). In the entire population and in children, respectively, outpatient antibiotic overuse attributable to viral LRTIs was estimated to be 289 (95% CI: 221, 374) and 1588 (95% CI: 1295, 1922) prescriptions per 100 000 inhabitants per week. These results highlight the major role of viral infections in driving antibiotic prescriptions, particularly in young children.

Background The recent emergence of strains belonging to the meningococcal serogroup W (MenW) sequence type-11 clonal complex and descending from the South American sub-lineage (MenW:cc11/SA) has caused significant shifts in the epidemiology of meningococcal disease worldwide. Although MenW:cc11/SA is deemed highly transmissible and invasive, its epidemiological characteristics have not yet been quantified. Methods We designed a mathematical model of MenW transmission, carriage, and infection to analyze the recent epidemiology of invasive disease caused by MenW:cc11/SA strains and by other MenW strains in England and in France. We confronted that model with age-stratified incidence data to estimate the transmissibility and the invasiveness of MenW:cc11/SA in England, using the data in France as a validation cohort. Results During the epidemiological years 2010/2011–2014/2015 in England, the transmissibility of MenW:cc11/SA relative to that of other MenW strains was estimated at 1.20 (95% confidence interval, 1.15 to 1.26). The relative invasiveness of MenW:cc11/SA was also found to exceed unity and to increase with age, with estimates ranging from 4.0 (1.6 to 9.7) in children aged 0–4 years to 20 (6 to 34) in adults aged ≥ 25 years. In France, the model calibrated in England correctly reproduced the early increase of MenW:cc11/SA disease during 2012/2013–2016/2017. Most recent surveillance data, however, indicated a decline in MenW:cc11/SA disease. In both countries, our results suggested that the transmission of MenW:cc11/SA carriage possibly started several months before the first reported case of MenW:cc11/SA disease. Discussion Our results confirm earlier suggestions about the transmission and the pathogenic potential of MenW:cc11/SA. The main limitation of our study was the lack of age-specific MenW carriage data to confront our model predictions with. Furthermore, the lesser model fit to the most recent data in France suggests that the predictive accuracy of our model might be limited to 5–6 years. Conclusions Our study provides the first estimates of the transmissibility and of the invasiveness of MenW:cc11/SA. Such estimates may be useful to anticipate changes in the epidemiology of MenW and to adapt vaccination strategies. Our results also point to silent, prolonged transmission of MenW:cc11/SA carriage, with potentially important implications for epidemic preparedness.

This work resulted from the MOD-COV Project (Modelling of the hOspital Dissemination of SARS-CoV-2), a collaboration between the Institut Pasteur, the Conservatoire Nationale des Arts et Métiers, and the AVIESAN/REACTing working group “Modelling SARS-CoV-2 dissemination in healthcare settings”, whose members we thank (Niccolo Buetti, Christian Brun-Buisson, Sylvie Burban, Simon Cauchemez, Guillaume Chelius, Anthony Cousien, Pascal Crepey, Vittoria Colizza, Christel Daniel, Aurélien Dinh, Pierre Frange, Eric Fleury, Antoine Fraboulet, Marie-Paule Gustin, Lidia Kardas-Sloma, Elsa Kermorvant, Jean Christophe Lucet, Chiara Poletto, Rodolphe Thiebaut, Sylvie van der Werf, Philippe Vanhems, Linda Wittkop, Jean-Ralph Zahar).We also thank the i-Bird Study Group (Anne Sophie Alvarez, Audrey Baraffe, Mariano Beiró, Inga Bertucci, Pierre-Yves Boëlle, Camille Cyncynatus, Florence Dannet, Marie Laure Delaby, Pierre Denys, Matthieu Domenech de Cellès, Eric Fleury, Antoine Fraboulet, Jean-Louis Gaillard, Boris Labrador, Jennifer Lasley, Christine Lawrence, Judith Legrand, Odile Le Minor, Caroline Ligier, Lucie Martinet, Karine Mignon, Catherine Sacleux, Jérôme Salomon, Thomas Obadia, Marie Perard, Laure Petit, Laeticia Remy, Anne Thiebaut, Damien Thomas, Philippe Tronchet, Isabelle Villain), as well as Jacob Barrett for helpful discussion.; International audience; Background: Long-term care facilities (LTCFs) are vulnerable to outbreaks of coronavirus disease 2019 (COVID-19). Timely epidemiological surveillance is essential for outbreak response, but is complicated by a high proportion of silent (non-symptomatic) infections and limited testing resources.Methods: We used a stochastic, individual-based model to simulate transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) along detailed inter-individual contact networks describing patient-staff interactions in a real LTCF setting. We simulated distribution of nasopharyngeal swabs and reverse transcriptase polymerase chain reaction (RT-PCR) tests using clinical and demographic indications and evaluated the efficacy and resource-efficiency of a range of surveillance strategies, including group testing (sample pooling) and testing cascades, which couple (i) testing for multiple indications (symptoms, admission) with (ii) random daily testing.Results: In the baseline scenario, randomly introducing a silent SARS-CoV-2 infection into a 170-bed LTCF led to large outbreaks, with a cumulative 86 (95% uncertainty interval 6-224) infections after 3 weeks of unmitigated transmission. Efficacy of symptom-based screening was limited by lags to symptom onset and silent asymptomatic and pre-symptomatic transmission. Across scenarios, testing upon admission detected just 34-66% of patients infected upon LTCF entry, and also missed potential introductions from staff. Random daily testing was more effective when targeting patients than staff, but was overall an inefficient use of limited resources. At high testing capacity (> 10 tests/100 beds/day), cascades were most effective, with a 19-36% probability of detecting outbreaks prior to any nosocomial transmission, and 26-46% prior to first onset of COVID-19 symptoms. Conversely, at low capacity (< 2 tests/100 beds/day), group testing strategies detected outbreaks earliest. Pooling randomly selected patients in a daily group test was most likely to detect outbreaks prior to first symptom onset (16-27%), while pooling patients and staff expressing any COVID-like symptoms was the most efficient means to improve surveillance given resource limitations, compared to the reference requiring only 6-9 additional tests and 11-28 additional swabs to detect outbreaks 1-6 days earlier, prior to an additional 11-22 infections.Conclusions: COVID-19 surveillance is challenged by delayed or absent clinical symptoms and imperfect diagnostic sensitivity of standard RT-PCR tests. In our analysis, group testing was the most effective and efficient COVID-19 surveillance strategy for resource-limited LTCFs. Testing cascades were even more effective given ample testing resources. Increasing testing capacity and updating surveillance protocols accordingly could facilitate earlier detection of emerging outbreaks, informing a need for urgent intervention in settings with ongoing nosocomial transmission.

OBJECTIVEGender disparities in neurosurgery have persisted even as the number of female medical students in many countries has risen. An understanding of the current gender distribution of neurosurgeons around the world and the possible factors contributing to country-specific gender disparities is an important step in improving gender equity in the field.METHODSThe authors performed a systematic review of studies pertaining to women in neurosurgery. Papers listed in PubMed in the English language were collected. A modified grounded theory approach was utilized to systematically identify and code factors noted to contribute to gender disparities in neurosurgery. Statistical analysis was performed with IBM SPSS Statistics for Windows.RESULTSThe authors identified 39 studies describing the density of women neurosurgeons in particular regions, 18 of which documented the proportion of practicing female neurosurgeons in a single or in multiple countries. The majority of these studies were published within the last 5 years. Eight factors contributing to gender disparity were identified, including conference representation, the proverbial glass ceiling, lifestyle, mentoring, discrimination, interest, salary, and physical burden.CONCLUSIONSThe topic of women in neurosurgery has received considerable global scholarly attention. The worldwide proportion of female neurosurgeons varies by region and country. Mentorship was the most frequently cited factor contributing to noted gender differences, with lifestyle, the glass ceiling, and discrimination also frequently mentioned. Future studies are necessary to assess the influence of country-specific sociopolitical factors that push and pull individuals of all backgrounds to enter this field.

The spread of carbapenemase-producing Enterobacteriaceae (CPE) in healthcare settings is a major public health threat that has been associated with cross-border and local patient transfers between healthcare facilities. Since the impact of transfers on spread may vary, our study aimed to assess the contribution of a patient transfer network on CPE incidence and spread at a countrywide level, with a case study of France from 2012 to 2015. Our results suggest a transition in 2013 from a CPE epidemic sustained by internationally imported episodes to an epidemic sustained by local transmission events through patient transfers. Incident episodes tend to occur within close spatial distance of their potential infector. We also observe an increasing frequency of multiple spreading events, originating from a limited number of regional hubs. Consequently, coordinated prevention and infection control strategies should focus on transfers of carriers of CPE to reduce regional and inter-regional transmission.

As in past pandemics, co-circulating pathogens may play a role in the epidemiology of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). Here we hypothesized that influenza interacted with SARS-CoV-2 during the early 2020 epidemic of COVID-19 in Europe. We developed a population-based model of SARS-CoV-2 transmission, combined with mortality incidence data in four European countries, to test a range of assumptions about the impact of influenza. We found consistent evidence for a 2–2.5-fold population-level increase in SARSCoV-2 transmission associated with influenza during the period of co-circulation. These results suggest the need to increase vaccination against influenza, not only to reduce the burden due to influenza viruses, but also to counteract their facilitatory impact on SARS-CoV-2.

Multiple myeloma (MM) is an almost always incurable malignancy of plasma cells. Despite the advent of new therapies, most patients eventually relapse or become treatment-refractory. Consequently, therapies with nonoverlapping mechanisms of action that are nontoxic and provide long-term benefit to patients with MM are greatly needed. To this end, we clinically tested an autologous multitumor-associated antigen (mTAA)-specific T cell product for the treatment of patients with high-risk, relapsed or refractory MM. In this study, we expanded polyclonal T cells from 23 patients with MM. T cells whose native T cell receptors were reactive toward five myeloma-expressed target TAAs (PRAME, SSX2, MAGEA4, Survivin, and NY-ESO-1) were enriched ex vivo. To date, we have administered escalating doses of these nonengineered mTAA-specific T cells (0.5 × 107 to 2 × 107 cells/m2) to 21 patients with MM, 9 of whom were at high risk of relapse after a median of 3 lines of prior therapy and 12 with active, relapsed or refractory disease after a median of 3.5 prior lines. The cells were well tolerated, with only two transient, grade III infusion-related adverse events. Furthermore, patients with active relapsed or refractory myeloma enjoyed a longer than expected progression-free survival and responders included three patients who achieved objective responses concomitant with detection of functional TAA-reactive T cell clonotypes derived from the infused mTAA product.

COVID-19 pandemic in France Coronavirus disease 2019 (COVID-19) exacted a heavy toll in France during March and April 2020. Quarantine measures were effective in reducing transmission by 84%, and some relaxation of social isolation was expected in May. Salje et al. fit transmission models for the epidemic in France to hospital admissions. The authors forecast that 2.9 million people will have been infected by 11 May, representing 4.4% of the population—a value inadequate for herd immunity. Daily critical care hospitalizations should reduce from several hundreds to tens of cases, but control will remain a delicate balancing act. Any relaxation of lockdown in France will have to be carefully controlled and monitored to avoid undermining more optimistic forecasts. Science , this issue p. 208

Aims: The aim of the study was to compare the genotoxic effect by assessing the micronucleus frequency (MNF), as a biomarker for DNA damage, in subjects with chronic periodontitis with and without type 2 Diabetes Mellitus. Methods and Material: For the study, a total of 65 subjects were take and divided into three groups. Group A included 30 subjects with Generalised Chronic Periodontitis, Group Bincluded 30 Subjects with Chronic Periodontitis with type 2 diabetes mellitus and Group C included 5 systemically and periodontally healthy subjects. Periodontal clinical examination was carried out. A slide was prepared using the blood sample collected from the subjects which was fixed in 5% geimsa solution and was observed under the microscope. Later the scoring of micronuclei was done. Statistical analysis used: Descriptive and inferential statistical analyses were carried out in the present study. Analysis of Variance (ANOVA) was used to find the significance of study parameters and test the equality of three or more means of more than two groups. Tukey’s post hoc analysis was used to compare parameters of each and every group. Results: The mean score of the micronuclei observed in group A, B and C were 10.23, 14.87 and 1 respectively i.e. group B showed significantly greater damage than other two groups. Conclusions: It was concluded that the score of micronucleus frequency may be considered as an important biomarker of genotoxic damage that is DNA damage in subjects with chronic localised as well as systemic diseases like type 2 diabetes, as well as Periodontal diseases.

Summary Background Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic. Methods In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed. Findings 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 837 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27–0·37]) and 82% at 8 weeks (0·18 [0·14–0·23]) following the week in which significant changes in population movements were recorded. Interpretation The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide. Funding Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Pública de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).

Glioblastoma is an aggressive central nervous system tumor with a 5-year-survival rate of less than 10%. Patients diagnosed with the disease are treated with surgery, radiation and temozolomide chemotherapy. Despite survival benefits, patients eventually relapse. There is a need for new treatments with improved efficacy. Imipridone ONC201 is a small molecule originally identified as a TNF-related apoptosis inducing ligand (TRAIL)-inducing compound. ONC201 has the unique ability to induce expression of both pro-death ligand TRAIL and its receptor DR5 through engagement of the cellular integrated stress response (ISR) pathway. Arrillaga-Romany et al. report early results from futility analysis of a phase II clinical trial of ONC201 in 17 patients with recurrent or refractory glioblastoma conducted at the Massachusetts General Hospital Cancer Center. The results are promising, as ONC201 shows preliminary signs of efficacy. Further testing of ONC201 in an expansion cohort of patients with glioblastoma is ongoing.

Background Host-level influenza virus–respiratory pathogen interactions are often reported. Although the exact biological mechanisms involved remain unelucidated, secondary bacterial infections are known to account for a large part of the influenza-associated burden, during seasonal and pandemic outbreaks. Those interactions probably impact the microorganisms’ transmission dynamics and the influenza public health toll. Mathematical models have been widely used to examine influenza epidemics and the public health impact of control measures. However, most influenza models overlooked interaction phenomena and ignored other co-circulating pathogens. Methods Herein, we describe a novel agent-based model (ABM) of influenza transmission during interaction with another respiratory pathogen. The interacting microorganism can persist in the population year round (endemic type, e.g. respiratory bacteria) or cause short-term annual outbreaks (epidemic type, e.g. winter respiratory viruses). The agent-based framework enables precise formalization of the pathogens’ natural histories and complex within-host phenomena. As a case study, this ABM is applied to the well-known influenza virus–pneumococcus interaction, for which several biological mechanisms have been proposed. Different mechanistic hypotheses of interaction are simulated and the resulting virus-induced pneumococcal infection (PI) burden is assessed. Results This ABM generates realistic data for both pathogens in terms of weekly incidences of PI cases, carriage rates, epidemic size and epidemic timing. Notably, distinct interaction hypotheses resulted in different transmission patterns and led to wide variations of the associated PI burden. Interaction strength was also of paramount importance: when influenza increased pneumococcus acquisition, 4–27% of the PI burden during the influenza season was attributable to influenza depending on the interaction strength. Conclusions This open-source ABM provides new opportunities to investigate influenza interactions from a theoretical point of view and could easily be extended to other pathogens. It provides a unique framework to generate in silico data for different scenarios and thereby test mechanistic hypotheses. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2464-z) contains supplementary material, which is available to authorized users.

Background. Serious viral infections associated with delayed immune reconstitution are a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). In approximately 90% of allogeneic HSCT patients, the suppressed immune system allows viruses that were previously in a latent, quiescent state to reactivate, with up to 60% of patients experiencing a reactivation of 2 or more viruses, including BKV, CMV, AdV, EBV and HHV-6; HSCT also predisposes for persistent acute infections, such as AdV. There is a lack of effective antiviral drugs to treat the majority of these infections and, when used clinically, available antiviral therapies are associated with significant toxicities, resulting in a substantial unmet medical need in this population. Viralym-M is an allogeneic, off-the-shelf multi-virus specific T cell (VSTs) product targeting five common viruses (BKV, CMV, AdV, EBV and HHV-6) that can lead to devastating diseases in allogeneic HSCT recipients. As T cells play a central role in response to viral infection, Viralym-M is intended to restore VST immunity to treat or prevent viral diseases and infections. Efficacy and safety of Viralym-M in allogeneic HSCT recipients with at least one treatment-refractory infection were evaluated in a phase II proof-of-concept trial (CHARMS study). In a previously published interim analysis from the study, infusion of Viralym-M was well tolerated and associated with clinical responses in most patients. Here we present the efficacy and safety data from the complete cohort of patients enrolled in the CHARMS study. Methods. Allogeneic HSCT patients who had either failed antiviral therapy or were unable to tolerate standard antivirals to control BKV, CMV, AdV, EBC, HHV-6, and/or JCV infection were enrolled to the study. Viralym-M was given as a single infusion of 2x107 VSTs/m2. If a partial response was achieved, patients could receive up to 4 additional doses after 4 weeks, at 2-week intervals. Study end points included resolution of the target infections as measured by viral load, resolution of clinical signs and symptoms as determined by the primary investigator, and safety. A complete response (CR) was defined as viral load returning to normal range and resolution of clinical signs/symptoms, while a partial response (PR) as a ≥50% decrease in viral load and/or 50% improvement of clinical signs/symptoms. Clinical end points were assessed by 6 weeks post infusion, and patients were followed until the end of study at 12 months. Persistence of the VSTs was examined by the epitope specificity of circulating T cells. Results. Fifty-eight patients were treated with Viralym-M, with one patient who was treated for two different infections separately (N=59). Nineteen (32.2%) were pediatric and 40 (67.8%) were adults. Of the patients with one viral infection, 30.5% had BKV, 28.8% CMV, 13.6% AdV, 5.1% HHV-6, 1.7% EBV, and 1.7% JCV. Eleven patients (18.6%) had more than one virus infection: 10 were co-infected with 2 different viruses, and 1 with 3 different viruses. The majority of patients received one infusion (74.6%). Overall, more than 90% of patients achieved a clinical response (PR or CR) by 6 weeks post Viralym-M infusion. 11 patients on the trial were co-infected with multiple viruses and 19 of the 23 viral infections in these patients responded to Viralym-M. We tested for persistence in 16 patients and 11 (69%) had circulating VSTs with persistence of VSTs of third party origin for up to 12 weeks. Treatment with Viralym-M was generally well tolerated. No immediate toxicities were observed and, other than isolated fever in a few patients, we observed no symptoms associated with CRS. Fourteen cases of acute graft-versus-host disease (GVHD) were observed; 8 of these were pre-existing. Of the six patients that experienced de novo GVHD, all had transient grade 1 skin GVHD that resolved with treatment. Conclusions. More than 90% of patients achieved a clinical response by 6 weeks post Viralym-M treatment, which was generally well tolerated, suggesting that Viralym-M can be safely and effectively used to treat viral infections, including multiple infections, in patients following allogeneic HSCT. Viralym-M has now received Regenerative Medicine Advanced Therapy (RMAT) and PRIority MEdicine (PRIME) designation from both the FDA and EMA. Phase 3 and proof-of-concept studies are in progress. Disclosures Tzannou: Allovir: Consultancy. Watanabe:AlloVir: Consultancy. Kuvalekar:AlloVir: Consultancy. Ramos:Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Kuur Therapeutics: Research Funding. Heslop:Novartis: Consultancy; Gilead Biosciences: Consultancy; PACT Pharma: Consultancy; Kiadis: Consultancy; Tessa Therapeutics: Consultancy, Research Funding; Marker Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; AlloVir: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Leen:AlloVir: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Omer:Allovir: Consultancy, Research Funding.

BACKGROUND Optune-delivered TTFields is a promising anti-mitotic FDA-approved cancer therapy in adult patients with high-grade gliomas (HGG), although effectiveness is not yet proven in pediatric patients. A multicenter trial [NCT03033992] evaluating the feasibility and device-related toxicity for children with recurrent or progressive supratentorial high-grade glioma (HGG) and ependymoma is being conducted. This presentation reports the interim health-related quality of life (HRQOL) and device-use experiences reported by patients and parents. METHODS Participating patients (aged 5–21 years) and one of their parents completed the following measures at baseline and prior to each intervention cycle: PROMIS Fatigue, Anger, Anxiety, Depressive Symptoms, Mobility, Upper Extremity Function, and Peer Relationships and Neuro-QOL Stigma. Participants completed an exit survey when they were off the study regarding their experiences wearing the device. RESULTS This planned interim analysis included 11 patients (7 males/4 females) with supratentorial tumors: ten HGG and one ependymoma. Median age was 14.2 (6.4–21.3) years. Patients reported worse HRQOL than the norms on all domains. Of these 11 patients, 6 completed the exit survey. No significant changes (p< 0.05) between the baseline and the final assessment were found except for Stigma. Patients perceived less stigma at baseline than at the final assessment (t=2.82, p=0.0370). Of these 6 parents who completed the Exit Survey: most considered wearing the device to be easy (n=5).Patient reminders were unnecessary (n=5), patients rarely/didn’t complain (n=4) or refuse (n=5) to wear the device, there was rare/no (n=4) difficulty with daily activities because of the device, and patients were not (n=4) or sometimes (n=2) embarrassed to wear the device. CONCLUSION Preliminary results indicate Optune-delivered TTFields therapy is feasible and accepted by children and parent with no evidence of negatively impacting patients’ QOL. Accrual has been expanded beyond the interim analysis.

BACKGROUND Pediatric high grade glioma (pHGG) remains a fatal disease. Access to richly annotated biospecimens and patient derived tumor models will accelerate pHGG research and support translation of research discoveries. This work describes the pediatric high grade glioma set of the Children’s Brain Tumor Tissue Consortium (CBTTC) from the first release of the Pediatric Brain Tumor Atlas (PBTA). METHODS pHGG tumors with associated clinical data and imaging were prospectively collected through the CBTTC and analyzed as the Pediatric Brain Tumor Atlas (PBTA) with processed genomic data deposited into PedcBioPortal for broad access and visualization. Matched tumor was cultured to create high grade glioma cell lines analyzed by targeted and WGS and RNA-seq. A tissue microarray (TMA) of primary pHGG tumors was also created. RESULTS The pHGG set includes 87 collection events (73 patients, 60% at diagnosis, median age of 9 yrs, 55% female, 46% hemispheric). Operative reports, pathology reports and histology images are available for nearly all cases. Pre- and post-operative MRI images and reports are also available for a subset. Tumor WGS/RNAseq is available for 70 subjects. Analysis of somatic mutations and copy number alterations of known glioma genes were of expected distribution (36% H3.3, 47% TP53, 24% ATRX and 7% BRAFV600E variants). In our panel of pHGG, six patients (8 tumors) harbored germline mismatch repair mutations with tumor hyper-mutation. A pHGG TMA (n=77), includes 36 patient tumors with matched sequencing. At least one established glioma cell line was generated from 23 patients (32%). Unique reagents include those derived from a H3.3 G34R glioma and from tumors with mismatch repair deficiency. CONCLUSION The CBTTC and PBTA have created an openly available integrated resource of over 2,000 tumors, including a rich set of pHGG primary tumors, corresponding cell lines and archival fixed tissue to advance translational research for pHGG.

BackgroundPediatric high grade glioma (pHGG) remains a fatal disease. Increased access to richly annotated biospecimens and patient derived tumor models will accelerate pHGG research and support translation of research discoveries. This work describes the pediatric high grade glioma set of the Children’s Brain Tumor Tissue Consortium (CBTTC) from the first release (October 2018) of the Pediatric Brain Tumor Atlas (PBTA).MethodspHGG tumors with associated clinical data and imaging were prospectively collected through the CBTTC and analyzed as the Pediatric Brain Tumor Atlas (PBTA) with processed genomic data deposited into PedcBioPortal for broad access and visualization. Matched tumor was cultured to create high grade glioma cell lines analyzed by targeted and WGS and RNA-seq. A tissue microarray (TMA) of primary pHGG tumors was also created.ResultsThe pHGG set included 87 collection events (73 patients, 60% at diagnosis, median age of 9 yrs, 55% female, 46% hemispheric). Analysis of somatic mutations and copy number alterations of known glioma genes were of expected distribution (36%H3.3, 47%TP53, 24%ATRXand 7%BRAFV600E variants). A pHGG TMA (n=77), includes 36 (53%) patient tumors with matched sequencing. At least one established glioma cell line was generated from 23 patients (32%). Unique reagents include those derived from aH3.3G34R glioma and from tumors with mismatch repair deficiency.ConclusionThe CBTTC and PBTA have created an openly available integrated resource of over 2,000 tumors, including a rich set of pHGG primary tumors, corresponding cell lines and archival fixed tissue to advance translational research for pHGG.IMPORTANCE OF STUDYHigh-grade gliomas (HGG) remain the leading cause of cancer death in children. Since molecularly heterogeneous, preclinical studies of pediatric HGG will be most informative if able to compare across groups. Given their relatively rarity, there are few readily available biospecimens and cellular models to inform preclinical laboratory and genomic translational research. Therefore, the aim of this CBTTC study was to highlight the panel of pediatric HGG cases whose primary tumors have undergone extensive genomic analysis, have clinical data, available imaging and additional biospecimens, including tumor, nucleic acids, cell lines and FFPE tissue on a tissue microarray (TMA).

The majority of patients with B-cell non-Hodgkin lymphoma (NHL) can be cured with standard chemoimmunotherapy. However, patients who fail first line therapy have dismal outcomes, particularly if they have disease that is resistant to salvage therapy, including chemoimmunotherapy, radiation and/or autologous stem cell transplantation. Indolent B-NHLs, such as follicular lymphoma (FL), although not generally considered curable may be treated over many years with good prognosis. However, a subset of B-NHLs can undergo histologic transformation into more aggressive subtypes with outcomes similar to aggressive B-NHLs. In recent years, T cells genetically modified with chimeric antigen receptors (CARs), have demonstrated a remarkable capacity to induce complete and durable clinical responses in patients with chemotherapy-refractory lymphomas. Indeed, two autologous CD19-directed CAR-modified T cell products have now been FDA-approved for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed FL, while a plethora of other CAR-T cell targets are being explored in ongoing clinical trials. The purpose of this review is to summarize the clinical efficacy and unique toxicities of individually developed CAR-T cell products for the treatment of lymphomas, and their evolution from the laboratory bench to commercialization.

The Pediatric Brain Tumor Atlas (PBTA), created as a multi-center effort by the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) and supported by the Gabriella Miller Kids First Data Resource Center (DRC), has the initial goal of comprehensively characterizing over 1,600 clinically annotated pediatric brain tumor samples and making the data publicly available to cancer researchers worldwide in near real time and without embargo. PBTA comprises comprehensive clinical data in addition to whole exome sequencing, whole genome sequencing (WGS), RNA sequencing (RNASeq), miRNA sequencing, and proteomics. To address the need to inform novel discovery and clinical implementation of genomic approaches for diagnostic/therapeutic purposes, PBTA utilizes the cloud-based research environment of the Gabriella Miller Kids First DRC to provide near real-time integration, dissemination, processing, and sharing of associated petabyte-scale harmonized data. The PBTA initiative leverages the DRC platform’s users to access their dbGAP approved use of TARGET and other pediatric cancer datasets hosted by NCI’s Cancer Genomics’ Cloud and Genomic Data Commons, allowing for cross-disease studies. Processed annotations is further enabled for the PBTA via PedcBioPortal, a data visualization/analysis application further integrating additional public and deposited datasets. In its first data release are over 30 different types of pediatric brain tumors representing over 1,000 subjects. This data is available on the Kids First DRC Portal and PedcBioPortal and users can seamlessly move between applications. Data types include those for matched tumor/normal samples, such as WGS, RNASeq, proteomics, longitudinal clinical data, imaging data (MRIs and radiology reports), histology slide images, and pathology reports. CBTTC/PNOC promote real-time data release and collaborative discovery via shared resources. The combination of cloud-based analytic platforms with data from both genomics and clinical practice serves to define a new paradigm for accelerated pediatric cancer translational research.

Background: Suicides by any method, plus ‘nonsuicide’ fatalities from drug self-intoxication (estimated from selected forensically undetermined and ‘accidental’ deaths), together represent self-injury mortality (SIM)—fatalities due to mental disorders or distress. SIM is especially important to examine given frequent undercounting of suicides amongst drug overdose deaths. We report suicide and SIM trends in the United States of America (US) during 1999–2018, portray interstate rate trends, and examine spatiotemporal (spacetime) diffusion or spread of the drug self-intoxication component of SIM, with attention to potential for differential suicide misclassification. Methods: For this state-based, cross-sectional, panel time series, we used de-identified manner and underlying cause-of-death data for the 50 states and District of Columbia (DC) from CDC's Wide-ranging Online Data for Epidemiologic Research. Procedures comprised joinpoint regression to describe national trends; Spearman's rank-order correlation coefficient to assess interstate SIM and suicide rate congruence; and spacetime hierarchical modelling of the ‘nonsuicide’ SIM component. Findings: The national annual average percentage change over the observation period in the SIM rate was 4.3% (95% CI: 3.3%, 5.4%; p6.0% increase (p

Aim The study was conducted to: (i) measure uterine volume in adolescent and perimenopausal age groups with normal pelvic findings and in women with pathological uteri scheduled for surgery, and (ii) utilize uterine volume as a parameter for the management of perimenopausal women scheduled for vaginal hysterectomy. Methods Data of 800 clinically non-gravid uteri of 16 weeks or smaller size with benign pathology scheduled for vaginal hysterectomy, and 150 adolescent women and 150 perimenopausal aged women with clinically and sonographically normal pelvic findings with normal uteri from the authors private practices were studied to find related sonographic uterine volume. Cases clinically more than 16 weeks size were not included in the study. Normal and pathological hysterectomized uteri were weighed postoperatively to compare their weight with preoperatively estimated uterine volume. Additionally, 200 pregnant women clinically diagnosed as 12 weeks pregnant and without pathology also underwent sonography to estimate their uterine volume. Results Uterine volume varied from 15 to 56 cm3 in women with a normal uterus. In 12 week sized non-pregnant benign pathological uteri, as well as pregnant uteri, uterine volume averaged 240 cm3. Uterine weight was higher when compared with preoperatively estimated uterine volume. Conclusions The study results emphasize uterine volume as an important parameter for the management of young and elderly women, particularly with menorrhagia. The uterus is anticipated to weigh more than the uterine volume, which can assist with diagnosis and management.

// Asneha Iqbal 1, 2 , Frank Eckerdt 1 , Jonathan Bell 1, 3 , Ichiro Nakano 4 , Francis J. Giles 1, 3 , Shi-Yuan Cheng 1 , Rishi R. Lulla 1, 2 , Stewart Goldman 1, 2 , Leonidas C. Platanias 1, 3, 5 1 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 2 Division of Hematology/Oncology/Stem Cell Transplantation, Ann and Robert H. Lurie Children’s Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 3 Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA 4 Department of Neurological Surgery and James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA 5 Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA Correspondence to: Leonidas C. Platanias, e-mail: l-platanias@northwestern.edu Keywords: glioblastoma, PIM kinase, mTOR signaling, p110α Received: February 04, 2016 Accepted: April 05, 2016 Published: April 21, 2016 ABSTRACT The PIM family of proteins encodes serine/threonine kinases with important roles in protein synthesis and cancer cell metabolism. In glioblastoma (GBM) cell lines, siRNA-mediated knockdown of PIM kinases or pharmacological inhibition of PIM kinases by SGI-1776 or AZD-1208 results in reduced phosphorylation of classic PIM effectors and also elements of the PI3K/mTOR pathway, suggesting interplay between PIM and mTOR signals in GBM cells. Combination of PIM kinase inhibitors with BYL-719, an inhibitor specific for the PI3K catalytic isoform p110α, results in enhanced antineoplastic effects in GBM cells. Additionally, pharmacologic inhibition of PIM kinases impairs growth of patient-derived glioma sphere cells, suggesting an important role for PIM kinases in cancer stem cell (CSC) function and survival. Such effects are further enhanced by concomitant inhibition of PIM kinase and p110α activities. Altogether these findings suggest that pharmacological PIM targeting in combination with PI3K inhibition may provide a unique therapeutic approach for the treatment of heterogeneous tumors containing populations of therapy-resistant CSCs in GBM.

Recent studies identified the presence of ALK/ROS/NTRK/MET alterations in a subset of infantile hemispheric gliomas. We report a case of GOPC-ROS1 fused congenital hemispheric glioma with a sustained response to crizotinib. An infant born at 28 weeks gestation was diagnosed with a large hemispheric mass at 2 weeks of life. The tumor was partially resected at 7 weeks of life. Histological evaluation confirmed a neoplasm with a spindle cell growth pattern, hypercellularity, nuclear pleomorphism, endothelial proliferation and necrosis consistent with glioblastoma. Fresh tissue was submitted for targeted panel sequencing (Oncopanel) which identified the presence of a GOPC-ROS1 fusion (exon 36:intron 4). This was confirmed by copy number analysis which showed a focal intragenic deletion with a breakpoint in ROS1 on 6q22. Given the lack of preclinical native models for ROS1 and other congenital kinase-driven gliomas, live cells were utilized to attempt to establish a patient derived cell line (organoid/neurosphere model) and intracranial patient derived xenograft model, the results of which are pending and will be reported. The GOPC-ROS1 rearrangement was structurally predicted to respond to kinase inhibitors with activity against ROS1 and crizotinib was started at 280 mg/m2/dose twice daily at 6 months of life with progressive tumor noted on imaging. Three months after initiating therapy, a 56% reduction in the tumor size and subsequent imaging revealed additional response. Our report is the first to demonstrate clinical response to crizotinib in a GPOC-ROS1 fused congenital glioblastoma and describe the development of a renewable resources for future analysis.

Infections caused by Streptococcus pneumoniae —including invasive pneumococcal diseases (IPDs)—remain a significant public health concern worldwide. The marked winter seasonality of IPDs is a striking, but still enigmatic aspect of pneumococcal epidemiology in nontropical climates. Here we confronted age-structured dynamic models of carriage transmission and disease with detailed IPD incidence data to test a range of hypotheses about the components and the mechanisms of pneumococcal seasonality. We find that seasonal variations in climate, influenza-like illnesses, and interindividual contacts jointly explain IPD seasonality. We show that both the carriage acquisition rate and the invasion rate vary seasonally, acting in concert to generate the marked seasonality typical of IPDs. We also find evidence that influenza-like illnesses increase the invasion rate in an age-specific manner, with a more pronounced effect in the elderly than in other demographics. Finally, we quantify the potential impact of seasonally timed interventions, a type of control measures that exploit pneumococcal seasonality to help reduce IPDs. Our findings shed light on the epidemiology of pneumococcus and may have notable implications for the control of pneumococcal infections.

Antibiotic-resistance of hospital-acquired infections is a major public health issue. The worldwide emergence and diffusion of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, including Escherichia coli (ESBL-EC) and Klebsiella pneumoniae (ESBL-KP), is of particular concern. Preventing their nosocomial spread requires understanding their transmission. Using Close Proximity Interactions (CPIs), measured by wearable sensors, and weekly ESBL-EC–and ESBL-KP–carriage data, we traced their possible transmission paths among 329 patients in a 200-bed long-term care facility over 4 months. Based on phenotypically defined resistance profiles to 12 antibiotics only, new bacterial acquisitions were tracked. Extending a previously proposed statistical method, the CPI network’s ability to support observed incident-colonization episodes of ESBL-EC and ESBL-KP was tested. Finally, mathematical modeling based on our findings assessed the effect of several infection-control measures. A potential infector was identified in the CPI network for 80% (16/20) of ESBL-KP acquisition episodes. The lengths of CPI paths between ESBL-KP incident cases and their potential infectors were shorter than predicted by chance (P = 0.02), indicating that CPI-network relationships were consistent with dissemination. Potential ESBL-EC infectors were identified for 54% (19/35) of the acquisitions, with longer-than-expected lengths of CPI paths. These contrasting results yielded differing impacts of infection control scenarios, with contact reduction interventions proving less effective for ESBL-EC than for ESBL-KP. These results highlight the widely variable transmission patterns among ESBL-producing Enterobacteriaceae species. CPI networks supported ESBL-KP, but not ESBL-EC spread. These outcomes could help design more specific surveillance and control strategies to prevent in-hospital Enterobacteriaceae dissemination., Author summary Tracing extended-spectrum β-lactamase (ESBL) dissemination in hospitals is an important step in the fight against the spread of multi-drug resistant bacteria. Indeed, understanding ESBL spreading dynamics will help identify efficient control interventions. In the i-Bird study, patients and hospital staff from a French long-term care facility carried a wearable sensor to capture their interactions at less than 1.5 meters, every 30 seconds over a 4-month period. Every week, patients were also swabbed to detect carriage of ESBL-producing Enterobacteriaceae. Based on the analysis of these longitudinal data, this study shows that ESBL-producing Klebsiella pneumoniae (ESBL-KP) mostly spreads during close-proximity interactions between individuals, while this is not the case for ESBL-producing Escherichia coli (ESBL-EC), suggesting that ESBL-KP but not ESBL-EC may be controlled by contact reduction interventions.

International audience; The diffusion of extended-spectrum beta-lactamase (E-ESBL)–producing Enterobacteriaceae is a major concern worldwide, especially in low-income countries, where they may lead to therapeutic failures. In hospitals, where colonization is the highest, E-ESBL transmission is poorly understood, limiting the possibility of establishing effective control measures. We assessed E-ESBL–acquisition routes in a neonatalogy ward in Madagascar. Individuals from a neonatology ward were longitudinally followed-up (August 2014–March 2015). Newborns’ family members’ and health-care workers (HCWs) were stool-sampled and tested for E-ESBL colonization weekly. Several hypothetical acquisition routes of newborns—e.g. direct contact with family members and HCWs and indirect contact with other newborns through environmental contamination, colonization pressure, or transient hand carriage—were examined and compared using mathematical modeling and Bayesian inference. In our results, high E-ESBL acquisition rates were found, reaching > 70% for newborns, > 55% for family members, and > 75% for HCWs. Modeling analyses indicated transmission sources for newborn colonization to be species dependent. Health-care workers’ route were selected for Klebsiella pneumoniae and Escherichia coli, with respective estimated transmission strengths of 0.05 (0.008; 0.14) and 0.008 (0.001; 0.021) ind−1 day−1. Indirect transmissions associated with ward prevalence, e.g. through hand carriage or environment, were selected for Enterobacter cloacae, E. coli, and K. pneumoniae (range 0.27–0.41 ind−1 day−1). Importantly, family members were not identified as transmission source. To conclude, E-ESBL acquisition sources are strongly species dependent. Escherichia coli and E. cloacae involve more indirect contamination, whereas K. pneumoniae also spreads through contact with colonized HCWs. These findings should help improve control measures to reduce in-hospital transmission.

Pediatric diffuse midline glioma is a highly morbid glial neoplasm that may arise in the thalamus or brainstem (also known as diffuse intrinsic pontine glioma or DIPG). Because tumor anatomic location precludes surgical resection, diagnosis and treatment is based on MR imaging and analysis of biopsy specimens. Up to 80% of pediatric diffuse midline gliomas harbor a histone H3 mutation resulting in the replacement of lysine 27 with methionine (K27M) in genes encoding histone H3 variant H3.3 (H3F3A) or H3.1 (HIST1H3B). H3K27M mutant glioma responds more poorly to treatment and is associated with worse clinical outcome than wild-type tumors, so mutation detection is now diagnostic for a new clinical entity, diffuse midline glioma H3K27M mutant, as defined in the most recent WHO classification system. We previously reported patterns of histone H3 trimethylation (H3K27me3) and acetylation (H3K27Ac) associated with H3K27M mutation that impact transcription regulation and contribute to tumorigenesis. Given the clinical implications of the H3K27M mutation and these associated H3 post-translational modifications (PTMs), we set to determine whether they can be characterized via immunohistochemistry (IHC) in a cohort of pediatric glioma (n = 69) and normal brain tissue (n = 4) specimens. We observed 100% concordance between tissue IHC and molecular sequencing for detecting H3K27M mutation. In turn, H3K37M and H3K27me3 results, but not H3K27Ac staining patterns, were predictive of clinical outcomes. Our results demonstrate H3K27M and H3K27me3 staining of pediatric glioma tissue may be useful for diagnosis, stratification to epigenetic targeted therapies, and longitudinal monitoring of treatment response.