Yin Li, Youming Wang, Chaojian Shen, Jianlong Huang, Jingli Kang, Baoxu Huang, Fusheng Guo, John Edwards

by Yin Li, Youming Wang, Chaojian Shen, Jianlong Huang, Jingli Kang, Baoxu Huang, Fusheng Guo, John Edwards Following the emergence of H7N9 influenza in March 2013, local animal and public health authorities in China have been closing live bird markets as a measure to try to control the H7N9 influenza epidemic. The role of live bird market (LBM) closure on the spread of N7N9 influenza following the closure of LBMs during March to May 2013 (the first wave) and October 2013 to March 2014 (the second wave) is described in this paper. Different provinces implemented closure actions at different times, and intensive media reports on H7N9 in different provinces started at different times. Local broiler prices dropped dramatically in places with outbreaks and more live chickens were transported to other LBMs in neighboring areas without human cases from infected areas when live bird markets were being closed. There were six clusters of human infection from March to May 2013 and October 2013 to March 2014 and there may have been intensive poultry transportation among cluster areas. These findings provide evidence that the closure of LBMs in early waves of H7N9 influenza had resulted in expansion of H7N9 infection to uninfected areas. This suggests that provincial authorities in inland provinces should be alert to the risks of sudden changes in movement patterns for live birds after LBM closure or increased publicity about LBM closure.

Ng T, Cowling B, Gao H, et al.

AbstractIntroductionA number of enhanced influenza vaccines have been developed for use in older adults, including the high-dose, MF59-adjuvanted, and intradermal vaccines. MethodsWe conducted a systematic review examining the improvements in antibody responses measured by the hemagglutination inhibition (HAI) assay associated with these enhanced vaccines, compared to each other, and compared to standard-dose vaccine using random effects models. ResultsThirty-nine trials were included. Compared to adults aged 60 years receiving standard-dose vaccines, those receiving enhanced vaccines had significantly higher post-vaccination titers (for all vaccine strains) and higher proportions with elevated titers ≥40 (for most vaccine strains). High-dose vaccine elicited 82% higher post-vaccination titer to A(H3N2) compared to standard-dose vaccine; this was significantly higher than 52% estimated for MF59-adjuvanted versus standard-dose vaccines (p=0.04), which was higher than 32% estimated for intradermal versus standard-dose vaccines (p

Abstract Background Nucleic acid amplification tests (NAAT) are well-accepted in diagnosis and surveillance of sexually infectious pathogens worldwide. However, performance differences between a RNA-based NAAT and DNA-based NAAT are rarely reported. This study compares the performances of the RNA-based SAT (simultaneous amplification and testing) assay and the DNA-based quantitative real-time polymerase chain reaction (qPCR) assay. Methods A total of 123 urogenital swabs were collected from outpatients with suspected genital infections in our hospital. Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Ureaplasma urealyticum (UU) in these swabs were simultaneously tested by SAT and qPCR. Any swabs were positive in the qPCR assay were further verified by following cloning and sequencing. All statistical analysis was performed using the SPSS software. Results When the concentrations of CT, NG, or UU were more than 1 × 103 copies/ml, 100% agreements between SAT and qPCR were observed regardless of the pathogen. No discrepancy was found. However, the sensitivity of SAT is significantly higher than qPCR in samples with concentration less than 1 × 103 copies/ml. When tested by SAT and qPCR, 57.14 and 28.57% were positive for CT, 46.15% and 0 were positive for NG, 80% and 0 were positive for UU, respectively. Conclusions The SAT assay has better agreements and higher sensitivities when compared with the qPCR assay, and thus could be a better choice for screening, diagnosis, and surveillance of sexually transmitted diseases, especially for CT and NG.…

Bauchner H, Fontanarosa PB, Flanagin A.

Conflict of interest affects virtually every aspect of medicine, including research, teaching, and clinical care. In May 2017, JAMA published a theme issue that included 23 articles on conflicts of interest (COIs) that represented “the multifaceted aspects and complexity of COI from numerous perspectives,” such as academia, medical education, medical practice, and research; industry payments to physicians and industry funding of and collaboration with researchers, guideline panels, professional associations, and academic medical centers; why COIs matter and how they are defined and managed; disclosures to patients; and the roles of journals and authors.

Danilo O. Carvalho, Samira Chuffi, Rafaella S. Ioshino, Isabel C. S. Marques, Regina Fini, Maria Karina Costa, Helena R. C. Araújo, André L. Costa-da-Silva, Bianca Burini Kojin, Margareth L. Capurro

by Danilo O. Carvalho, Samira Chuffi, Rafaella S. Ioshino, Isabel C. S. Marques, Regina Fini, Maria Karina Costa, Helena R. C. Araújo, André L. Costa-da-Silva, Bianca Burini Kojin, Margareth L. Capurro…

Can Liu, Wennan Wu, Shongyan Shang, Er Huang, Zhen Xun, Jinpiao Lin, Tianbin Chen, Bin Yang, Jing Chen, Qishui Ou

Cover Caption: The cover image is based on the Research Article Application strategies of serum HBV DNA detection in HBV infection patients: A retrospective study of 5611 specimens, by Can Liu et al., DOI 10.1002/jmv.25271.

Matharu, N., Rattanasopha, S., Tamura, S., Maliskova, L., Wang, Y., Bernard, A., Hardin, A., Eckalbar, W. L., Vaisse, C., Ahituv, N.

A wide-range of human diseases result from haploinsufficiency, where the function of one of the two gene copies is lost. Here, we targeted the remaining functional copy of a haploinsufficient gene using CRISPR-mediated activation (CRISPRa) in Sim1 and Mc4r heterozygous mouse models to rescue their obesity phenotype. Transgenic-based CRISPRa targeting of the Sim1 promoter or its distant hypothalamic enhancer upregulated its expression from the endogenous functional allele in a tissue-specific manner, rescuing the obesity phenotype in Sim1 heterozygous mice. To evaluate the therapeutic potential of CRISPRa, we injected CRISPRa-rAAV into the hypothalamus, which led to reversal of the obesity phenotype in Sim1 and Mc4r haploinsufficient mice. Our results suggest that endogenous gene upregulation could be a potential strategy to treat altered gene dosage diseases.…

Abstract Background Dengue Virus (DENV) and Zika Virus (ZIKV) are closely related flaviviruses, circulating in overlapping geographical regions. The recent ZIKV epidemic has been linked to an explosion in reports of microcephaly and neurological defects. It is conceivable that our knowledge of DENV might potentiate the development of a ZIKV vaccine due to the close phylogenetic relationship between these flaviviruses and cross-reactive antibodies, principally to the envelope protein (E protein). Alternatively, cross-reactive antibodies that are generated following vaccination or infection, might become damaging during subsequent infections. Main body The aims of this review are to collate and analyse data from a recent series of DENV-derived monoclonal antibody (mAb) panels from different research groups. These panels measured DENV-mAb activity against ZIKV in terms of antibody-dependent enhancement (ADE) and neutralisation. Methodology used across groups was compared and critiqued. Furthermore, the specific antibody targets on E protein were considered and their therapeutic potential evaluated. Shortcomings of hmAb panels suggest ADE may be over-estimated and neutralisation underestimated, as compared to clinical situations. It remains unknown whether preference of enhancement or neutralisation by antibodies to ZIKV E protein is dictated by quantitative aspects of antibody titre or epitope specific variation. Additionally, little is known about how duration between flavivirus reinfections affect secondary antibody response. Conclusion This review concludes that our current knowledge of cross-reactive antibodies to E protein is inadequate to anticipate the outcome of deploying an E protein based vaccine to regions co-infected by DENV and ZIKV.…

Filipe Dantas-Torres, Guadalupe Miró, Dwight D. Bowman, Luigi Gradoni, Domenico Otranto

Visceral leishmaniasis, caused by Leishmania infantum, is a zoonosis, and culling seropositive dogs has been recommended to control the disease in some endemic countries. However, no scientific evidence supports the effectiveness of this strategy to reduce the incidence of visceral leishmaniasis. Economic and ethical issues concerning dog culling are discussed.

Ann Chen Wu

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 12, Page e116-e136, December 15, 2018. …

Juan Pablo Gomez, Dawn M. Nekorchuk, Liang Mao, Sadie J. Ryan, José Miguel Ponciano, Jason K. Blackburn

by Juan Pablo Gomez, Dawn M. Nekorchuk, Liang Mao, Sadie J. Ryan, José Miguel Ponciano, Jason K. Blackburn Quantitative models describing environmentally-mediated disease transmission rarely focus on the independent contribution of recruitment and the environment on the force of infection driving outbreaks. In this study we attempt to investigate the interaction between external factors and host’s population dynamics in determining the outbreaks of some indirectly transmitted diseases. We first built deterministic and stochastic compartmental models based on anthrax which were parameterized using information from literature and complemented with field observations. Our force of infection function was derived modeling the number of successful transmission encounters as a pure birth process that depends on the pathogen’s dispersion effort. After accounting for individual heterogeneity in pathogen’s dispersion effort, we allowed the force of infection to vary seasonally according to external factors recreating a scenario in which disease transmission increases in response to an environmental variable. Using simulations we demonstrate that anthrax disease dynamics in mid-latitude grasslands is decoupled from hosts population dynamics. When seasonal forcing was ignored, outbreaks matched hosts reproductive events, a scenario that is not realistic in nature. Instead, when allowing the force of infection to vary seasonally, outbreaks were only present in years were environmental variables were appropriate for the outbreaks to develop. We used the stochastic formulation of the force of infection to derive R0 under scenarios with different assumptions. The derivation of R0 allowed us to conclude that during epizootic years, pathogen contribution to disease persistence is nearly independent of dispersion. In endemic years, only pathogens with high dispersion significantly prevent disease extinction. Finally, we used our model in a maximum likelihood framework to estimate the parameters that determined a significant anthrax outbreak in Montana in 2008. Our study highlights the importance of the environment in determining anthrax outbreak intensity and could be useful to predict future events that could result in significant wildlife and domestic livestock losses.

Abstract Background Although the incidence of dengue across Africa is high, severe dengue is reported infrequently. We describe the clinical features and the outcome of dengue according to raceduring an outbreak in Dar es Salaam, Tanzania that occurred in both native and expatriate populations. Methods Adults with confirmed dengue (NS1 and/or IgM on rapid diagnostic test and/or PCR positive) were included between December 2013 and July 2014 in outpatient clinics. Seven-day outcome was assessed by a visit or a call. Association between black race and clinical presentation, including warning signs, was assessed by logistic regression adjusted for age, malaria coinfection, secondary dengue and duration of symptoms at inclusion. The independent association between demographic and comorbidities characteristics of the patients and severe dengue was evaluated by multivariate logistic regression that included potential confounders. Results After exclusion of 3 patients of mixed race, 431 patients with dengue (serotype 2, genotype Cosmopolitan) were included: 241 of black and 190 of non-black race. Black patients were younger (median age 30 versus 41 years; p 

Mollett G, Bremer Hinckel B, Bhattacharyya T, et al.

AbstractBackgroundVisceral leishmaniasis (VL), caused by the Leishmania donovani complex, is a fatal neglected tropical disease that is targeted for elimination in India, Nepal and Bangladesh. Improved diagnostic tests are required for early case detection and for monitoring outcome of treatment. Previous investigations using Leishmania lysate antigen demonstrated that IgG1 response is a potential indicator of clinical status after chemotherapy.MethodsIgG1 or IgG ELISAs with rK39 or lysate antigens, and novel IgG1 rK39 rapid diagnostic tests (RDTs) were assessed with Indian VL serum samples from the following clinical groups: paired pre- and post-chemotherapy (deemed cured); relapsed; other infectious diseases, and endemic healthy controls.ResultsWith paired pre- and post-treatment samples (n = 37 pairs), ELISAs with rK39 and IgG1-specific conjugate gave a far more discriminative decrease in post-treatment antibody response when compared to IgG (p

Clapham H.

Mbisa J, Kirwan P, Tostevin A, et al.

AbstractBackgroundDrug-resistant minority variants (DRMinVs) detected in patients who recently acquired HIV-1 can be transmitted, generated de novo through virus replication, or technical errors. The first are likely to persist and result in treatment failure while the latter two could be stochastic and transient. MethodsUltra-deep sequencing of plasma samples from 835 individuals with recent HIV-1 infection in the UK was performed to detect DRMinVs at mutation frequency between 2-20%. Sequence alignments including >110,000 HIV-1 partial pol consensus sequences from the UK HIV Drug Resistance Database (UK-HDRD) , linked to epidemiological and clinical data from the HIV and AIDS Reporting System (HARS),were used for transmission cluster analysis. Transmission clusters were identified using Cluster Picker with a clade support of >90% and maximum genetic distances of 4.5% or 1.5%, the latter to limit detection to likely direct transmission events.ResultsDrug-resistant majority variants (DRMajVs) were detected in 66 (7.9%) and DRMinVs in 84 (10.1%) of the recently infected individuals. High levels of clustering to sequences in UK-HDRD were observed for both DRMajV (n=48; 72.7%) and DRMinV (n=63; 75.0%) sequences. Of these, 43 (65.2%) with DRMajVs were in a transmission cluster with sequences that harboured the same DR mutation compared to only 3 (3.6%) sequences with DRMinVs (p

Meagan Zarwell, William T. Robinson

by Meagan Zarwell, William T. Robinson Despite previous empirical studies which have linked social capital to a number of health outcomes, few studies have investigated sub-group specific social capital among populations at increased risk for HIV infection such as gay, bisexual and other men who have sex with men (GBM). Many GBM of color belong to constructed families in which friends refer to each other with kinship terms such as parents and children. No studies have measured social capital provisions within constructed family networks. This study developed a preliminary instrument for assessing social capital among constructed families. The network level social capital scale incorporated the following theoretical domains hypothesized to define social capital derived from network membership: social influence, multiplex ties, heterogeneity, social cohesion, trust, quality of support, and compositional quality. A cross-sectional survey administered an eight-item scale to 131 GBM who belonged to constructed families. The factor structure and confirmatory factor analysis were assessed. Reliability was evaluated using Cronbach’s alpha to measure internal consistency. A final single factor solution was obtained which was comprised of six items with high factor loadings. The resulting measures were highly correlated with an alpha of 0.84 and each factor loading was well above 0.3. This study assessed the psychometric properties of a preliminary network level social capital instrument among GBM in constructed families. Future studies may utilize or adopt this scale to measure network-level social capital within other populations.

Yang Liu, Nicolas Margot, Kathryn M. Kitrinos, Christian Callebaut

Abstract An HIV‐1 integrase (IN) genotyping assay was developed to evaluate clinical samples from patients infected with HIV‐1 subtype AE, a subtype highly prevalent in Asia. The HIV‐1 integrase gene was amplified from plasma‐derived HIV‐1 viral RNA via RT‐PCR followed by population sequencing. Assay sensitivity was also evaluated using serially diluted plasma samples. The genotyping assay successfully amplified the IN gene from patient plasma samples with HIV‐1 RNA as low as 500 copies/mL. This assay is suitable for IN genotyping to identify IN drug resistance mutations in HIV‐1 patients harboring subtype AE virus. This article is protected by copyright. All rights reserved.

Abstract Background This study seeks to compare the performance of HRP2 (First Response) and pLDH/HRP2 (Combo) RDTs for falciparum malaria against microscopy and PCR in acutely ill febrile children at presentation and follow-up. Methods This is an interventional study that recruited children 

Pecora, N., Zhao, X., Nudel, K., Hoffmann, M., Li, N., Onderdonk, A. B., Yokoe, D., Brown, E., Allard, M., Bry, L.

New Delhi metallo-beta-lactamases (NDMs) are an uncommon but emerging cause of carbapenem resistance in the United States. Genomic factors promoting their domestic spread remain poorly characterized. A prospective genomic surveillance program among Boston-area hospitals identified multiple new occurrences of NDM carrying strains of E. coli and E. cloacae complex in inpatient and outpatient settings, representing the first occurrences of NDM-mediated resistance since initiating genomic surveillance in 2011. Cases included domestic patients with no international exposures. PacBio sequencing of isolates identified strain characteristics, resistance genes, and the complement of mobile vectors mediating spread. Analyses revealed a common 3114-bp region containing the blaNDM gene, with carriage of this conserved region among unique strains by diverse transposon and plasmid backbones. Functional studies revealed broad capacity for blaNDM transmission by conjugation, transposition, and complex inter-plasmid recombination events. NDMs represent a rapidly spreading form of drug resistance that can occur in inpatient and outpatient settings and in patients without international exposures. In contrast to Tn4401-based spread of Klebsiella pneumoniae carbapenemases (KPCs), diverse transposable elements mobilize NDM enzymes, commonly with other resistance genes, enabling naïve strains to acquire multi- and extensively-drug resistance profiles with single transposition or plasmid conjugation events. Genomic surveillance provides effective means to rapidly identify these gene-level drivers of resistance and mobilization, to inform clinical decisions to prevent further spread.…

Kara N. Goss

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 12, Page 1549-1558, December 15, 2018. …

Pasayan, Mark Kristoffer U.; Mationg, Mary Lorraine S.; Boettiger, David; Lam, Wilson; Zhang, Fujie; Wen-Wei Ku, Stephane; Merati, Tuti Parwati; Chaiwarith, Romanee; Cuong, Do Duy; Yunihastuti, Evy; Kiertiburanakul, Sasisopin; Van Kinh, Nguyen; Avihingsanon, Anchalee; Sun, Ly Penh; Kamarulzaman, Adeeba; Kantipong, Pacharee; Kumarasamy, Nagalingeswaran; Pujari, Sanjay; Heng Sim, Benedict Lim; Ng, Oon Tek; Choi, Jun Yong; Tanuma, Junko; Ross, Jeremy; Ditangco, Rossana

Background: Mycobacterium avium complex (MAC) prophylaxis is recommended for patients with advanced HIV infection. With the decrease in incidence of disseminated MAC infection and the availability of antiretroviral therapy (ART), the benefits of macrolide prophylaxis were investigated. This study examined the impact of macrolide prophylaxis on AIDS-defining conditions and HIV-associated mortality in a cohort of HIV-infected patients on ART. Methods: Patients from TREAT Asia HIV Observational Database (September 2015 data transfer) aged ≥18 years with a CD4 count…

Stunnenberg BC, Raaphorst J, Groenewoud HM, et al.

This study uses a series of aggregated N-of-1 trials to investigate the effectiveness of mexiletine for treatment of muscle stiffness in adult patients with nondystrophic myotonia and compares results from this series with those from a previously conducted randomized clinical trial.

, Shoji T, Inaba M, et al.

This randomized, open-label, blinded end point randomized clinical trial examined the effect of oral alfacalcidol, a vitamin D receptor activator, on cardiovascular events in patients with cardiovascular kidney disease receiving hemodialysis.

Aboumatar H, Naqibuddin M, Chung S, et al.

This randomized clinical trial compares the effects of a program combining transition and long-term self-management support vs transition support alone on 6-month hospitalizations and emergency department visits among patients with chronic obstructive pulmonary disease (COPD).

Wendel Coura-Vital, Gleisiane Gomes de Almeida Leal, Luana Araújo Marques, Aimara da Costa Pinheiro, Mariângela Carneiro, Alexandre Barbosa Reis

by Wendel Coura-Vital, Gleisiane Gomes de Almeida Leal, Luana Araújo Marques, Aimara da Costa Pinheiro, Mariângela Carneiro, Alexandre Barbosa Reis To reduce morbidity and mortality caused by visceral leishmaniasis (VL), the Brazilian Visceral Leishmaniasis Control and Surveillance Program promotes the diagnosis and treatment of cases, vector control, euthanasia of seropositive dogs, and health education. Nevertheless, the effectiveness of these measures is questionable as they lead to little reduction in the transmission of the disease. Thus, the effectiveness of strategies such as insecticide-impregnated collars, spot-on insecticides, and immunization of dogs should be assessed. Herein, we evaluated the effectiveness of deltamethrin-impregnated collars on reducing the incidence of Leishmania infantum infection in dogs living in an endemic area of VL. An intervention study was conducted and a total 5,850 dogs were analyzed in baseline. Of these 3,742 seronegative dogs were divided into two groups: collared and uncollared (control). Dogs were followed for 12 months and three interventions were performed. The Cox regression model was used to evaluate the effectiveness of the collar. All analyzes were performed by Intention-to-treat and per-protocol. By intention-to-treat, the incidence rates of L. infantum infection were 7.5 and 7.9 in the collar group, and 6.5 and 13.2 per 1,000 dogs-months in the control group after 6 and 12 months, respectively. In the per-protocol analysis, the incidence rates in the control group were similar to those observed in the intention-to-treat analysis. In the collar group, the incidence rate was 5.1/1,000 dogs-months after 6 and 12 months. The effectiveness by intention-to-treat after adjustment by the multivariate Cox model was 48%. In the analysis per-protocol, the effectiveness increased to 63%. Although collar use was effective when it was evaluated by intention-to-treat, higher effectiveness was found in the per-protocol analysis after one year of follow-up. The data emphasize the importance of the uninterrupted use of deltamethrin-impregnated collars to increase protection against canine VL.

Abstract Background To combat emerging drug resistance in the Greater Mekong Sub-region (GMS) the World Health Organization and GMS countries have committed to eliminating malaria in the region by 2030. The overall approach includes providing universal access to diagnosis and treatment of malaria, and sustainable preventive measures, including vector control. Topical repellents are an intervention that can be used to target residual malaria transmission not covered by long lasting insecticide nets and indoor residual spraying. Although there is strong evidence that topical repellents protect against mosquito bites, evidence is not well established for the effectiveness of repellents distributed as part of malaria control activities in protecting against episodes of malaria. A common approach to deliver malaria services is to assign Village Health Volunteers (VHVs) to villages, particularly where limited or no services exist. The proposed trial aims to provide evidence for the effectiveness of repellent distributed through VHVs in reducing malaria. Methods The study is an open stepped-wedge cluster-randomised controlled trial randomised at the village level. Using this approach, repellent (N,N-diethyl-benzamide – 12% w/w, cream) is distributed by VHVs in villages sequentially throughout the malaria transmission season. Villages will be grouped into blocks, with blocks transitioned monthly from control (no repellent) to intervention states (to receive repellent) across 14 monthly intervals in random order). This follows a 4-week baseline period where all villages do not receive repellent. The primary endpoint is defined as the number of individuals positive for Plasmodium falciparum and Plasmodium vivax infections diagnosed by a rapid diagnostic test. Secondary endpoints include symptomatic malaria, Polymerase Chain Reaction (PCR)-detectable Plasmodium spp. infections, molecular markers of drug resistance and antibodies specific for Plasmodium spp. parasites. Discussion This study has been approved by relevant institutional ethics committees in Myanmar and Australia. Results will be disseminated through workshops, conferences and peer-reviewed publications. Findings will contribute to a better understanding of the optimal distribution mechanisms of repellent, context specific effectiveness and inform policy makers and implementers of malaria elimination programs in the GMS. Trial registration Australian and New Zealand Clinical Trials Registry (ACTRN12616001434482). Retrospectively registered 14th October 2016.…

Ayman Yosry, Hadeel Gamal Eldeen, Eman Medhat, Mai Mehrez, Naglaa Zayed, Wafaa Elakel, Reham Abdelmoniem, Mona Kaddah, Ashraf Abdelaziz, Gamal Esmat, Magdy EL‐Serafy, Wahid Doss

Background and Aim Direct acting antiviral has offered treatment of hepatitis C virus (HCV) recurrence post liver transplantation (LT) with an all‐oral regimen for short duration, excellent safety profile, and high sustained virological response (SVR). The aim of this study was to evaluate the efficacy and safety of sofosbuvir (SOF)‐based regimens in the real world among a cohort of Egyptian patients with recurrent HCV post living donor LT (LDLT). Methods Patients with HCV‐G4 recurrence post‐LDLT were recruited from National Committee of Control of Viral Hepatitis, Egypt, from November 2014 to May 2017. They received different SOF‐based regimens according to the treatment protocols available during this period. Patients’ outcome and Adverse effects (AE) were evaluated. Results One hundred ninety patients (170 males, mean age 56.8 ± 7.9 years) were included. Calcineurin inhibitors were the main immunosuppression used (173 patients). Out of 190, 119 (62.6%) received SOF/ribavirin (RBV), 38 (20%) SOF/simeprevir (SMV), 22 (11.6%) SOF/daclatasvir (DSV)/ ± RBV, and 11 (5.8%) received SOF/LDV/ ± RBV. Overall SVR12 was 89.5%, 84.9% in SOF/RBV group, 94.7% in SOF/SMV, 100% in SOF/DCV, and 100% in SOF/LDV with no statistically significant difference ( P = 0.104). The AE reported were as follows: anemia (n = 65, 34.4%) mainly in SOF/RBV group, transient hyperbilirubinemia during SOF/SMV in 13 patients (34%), mild Acute cellular rejection in eight patients (4.2%), and hepatocellular carcinoma in two patients (1%) mainly driven by underlying liver condition. Two deaths were unlikely related to HCV therapy. Conclusion Different SOF‐based regimens were effective with high SVR12 rates in a difficult‐to‐treat population, recurrent HCV post LDLT.

Tristan Cordier, Anders Lanzén, Laure Apothéloz-Perret-Gentil, Thorsten Stoeck, Jan Pawlowski

Genomics is fast becoming a routine tool in medical diagnostics and cutting-edge biotechnologies. Yet, its use for environmental biomonitoring is still considered a futuristic ideal. Until now, environmental genomics was mainly used as a replacement of the burdensome morphological identification, to screen known morphologically distinguishable bioindicator taxa. While prokaryotic and eukaryotic microbial diversity is of key importance in ecosystem functioning, its implementation in biomonitoring programs is still largely unappreciated, mainly because of difficulties in identifying microbes and limited knowledge of their ecological functions.

Xu, P., Ganaie, S. S., Wang, X., Wang, Z., Kleiboeker, S., Horton, N. C., Heier, R. F., Meyers, M. J., Tavis, J. E., Qiu, J.

Human parvovirus B19 (B19V), a member of the genus Erythroparvovirus of the family Parvoviridae, is a small non-enveloped virus that has a single-stranded DNA (ssDNA) genome of 5.6 kilobases with two inverted terminal repeats (ITRs). B19V infection often results in severe hematological disorders and fetal death in humans. B19V replication follows a model of rolling hairpin-dependent DNA replication, in which the large non-structural protein NS1 introduces a site-specific single strand nick in the viral DNA replication origins, which locate at the ITRs. NS1 executes endonuclease activity through the N-terminal origin binding domain. Nicking of the viral replication origin is a pivotal step in rolling hairpin-dependent viral DNA replication. Here, we developed a fluorophore-based in vitro nicking assay of the replication origin using the origin binding domain of the NS1 and compared it with the radioactive in vitro nicking assay. We used both assays to screen a set of small molecule compounds (96) that have potential anti-nuclease activity. We found that the fluorophore-based in vitro nicking assay demonstrate sensitivity and specificity values as high as the radioactive assay. Among the 96 compounds, we identified 8 which have an inhibition of >80% at 10 µM in both the fluorophore-based and radioactive in vitro nicking assays. We further tested 3 compounds that have flavonoid-like structure for IC50 in vitro that falls in the range of 1-3 µM. Importantly, they also exhibited inhibition of B19V DNA replication in UT7/Epo-S1 cells and ex vivo expanded human erythroid progenitor cells.…

C. Taravilla et al.

Jiangping Ren, Feng Ling, Jimin Sun, Zhenyu Gong, Ying Liu, Xuguang Shi, Rong Zhang, Yujia Zhai, Enfu Chen, Zhiping Chen

by Jiangping Ren, Feng Ling, Jimin Sun, Zhenyu Gong, Ying Liu, Xuguang Shi, Rong Zhang, Yujia Zhai, Enfu Chen, Zhiping Chen Background Dengue is one of the most important vector-bore infectious diseases in China because of its drastic increase in incidence, geographic extension and profound influence on China’s economy. This study aims to retrospectively uncover the epidemiological profile of dengue in Zhejiang, one of the most developed provinces in China, and to find the problem existing in dengue control and prevention. Methodology Descriptive analyses on the dengue incidence and associated factors were performed. We also identified potential space-time cluster and generated the risk map of dengue. Principal findings A total of 529 cases were reported in Zhejiang Province from 2005 to 2016, and 44.4% were imported. 67.7% of cases were 25~60 years old and the overall male-to-female sex ratio was 1.09:1. Dengue was reported all year round and 70.7% of cases occurred between August and October. Indigenous cases were only reported in the period between July to November and more than half occurred in September. Geographically, dengue was most distributed in Jinghua (3.62 per million), Shaoxing (1.00 per million) and Taizhou (0.81 per million) prefecture level cities. Outbreaks were confirmed in Yiwu, Keqiao and Huangyan counties in 2009, 2015, and 2016, respectively. 73.9% cases would seek medical advice within two days after onset and be confirmed within 9 days after onset. 75.6% would be recognized as dengue within 8 days after their first visit. The time intervals between onset and confirmation (median 7 vs 6 days; Wilcoxon rank sum test Z = -2.40, P = 0.016), first visit and confirmation (median 7 vs 6 days; Wilcoxon rank sum test Z = -2.59, P = 0.009) of indigenous cases were significantly longer than those of imported ones. However, the time intervals between onset and first visit for indigenous cases was shorter (median 0 vs 1 days; Wilcoxon rank sum test Z = -2.10, P = 0.036). Fever (99.1%), fatigue (81.9), rash (63.7%), headache (67.2%) and myalgia (52.60%) were the most frequently mentioned symptoms. Conclusions Zhejiang has recently witnessed an increase in incidence and geographic extension of dengue. Timely diagnosis is important to stop local transmission and outbreak.…

Adrienne Vickers, John P. Donnelly, Justin Xavier Moore, Scott R. Barnum, Theresa N. Schein, Henry E. Wang

by Adrienne Vickers, John P. Donnelly, Justin Xavier Moore, Scott R. Barnum, Theresa N. Schein, Henry E. Wang Objectives Lumbar puncture (LP) is an important technique for assessing and treating neurological symptoms. The objective of this study was to describe the characteristics of diagnostic lumbar punctures performed on hospitalized patients in the United States. Methods We analyzed data from the 2010 National Inpatient Sample (NIS) and the National Emergency Department Survey (NEDS). We included patients treated in the Emergency Department (ED) as well as those admitted to an inpatient bed through the ED. We identified patients undergoing LPs from ICD-9 procedural code 03.31 and CPT code 62270. We generated nationally weighted estimates of the total number of LPs. We also assessed patient and hospital characteristics of cases undergoing LP. Results Of an estimated 135 million hospitalizations (ED + admission, or ED only), there were an estimated 362,718 LPs (331,248–394,188), including 273,612 (251,850–295,375) among adults and 89,106 (71,870–106,342) among children (…

Robert Mertens, Sarah Melchert, Daniel Gitler, Morten Brix Schou, Sverre Georg Saether, Arne Vaaler, Johannes Piepgras, Elena Kochova, Fabio Benfenati, Gudrun Ahnert-Hilger, Klemens Ruprecht, Markus Höltje

by Robert Mertens, Sarah Melchert, Daniel Gitler, Morten Brix Schou, Sverre Georg Saether, Arne Vaaler, Johannes Piepgras, Elena Kochova, Fabio Benfenati, Gudrun Ahnert-Hilger, Klemens Ruprecht, Markus Höltje Objective To identify the specific domains of the presynaptic protein synapsin targeted by recently described autoantibodies to synapsin. Methods Sera of 20 and CSF of two patients with different psychiatric and neurological disorders previously tested positive for immunoglobulin (Ig)G antibodies to full-length synapsin were screened for IgG against synapsin I domains using HEK293 cells transfected with constructs encoding different domains of rat synapsin Ia. Additionally, IgG subclasses were determined using full-length synapsin Ia. Serum and CSF from one patient were also screened for IgA autoantibodies to synapsin I domains. Sera from nine and CSF from two healthy subjects were analyzed as controls. Results IgG in serum from 12 of 20 IgG synapsin full-length positive patients, but from none of the healthy controls, bound to synapsin domains. Of these 12 sera, six bound to the A domain, five to the D domain, and one to the B- (and possibly A-), D-, and E-domains of synapsin I. IgG antibodies to the D-domain were also detected in one of the CSF samples. Determination of IgG subclasses detected IgG1 in two sera and one CSF, IgG2 in none of the samples, IgG3 in two sera, and IgG4 in eight sera. One patient known to be positive for IgA antibodies to full-length synapsin had IgA antibodies to the D-domain in serum and CSF. Conclusions Anti-synapsin autoantibodies preferentially bind to either the A- or the D-domain of synapsin I.…

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 12, Page 1590-1590, December 15, 2018. …

In the Original Investigation titled “Association of Hospital Participation in a Medicare Bundled Payment Program With Volume and Case Mix of Lower Extermity Joint Replacement Episodes,” published in the September 4, 2018, issue of JAMA, data in a table and in the Results section were incorrect. In the “Complicated” row of Table 4, the means per 1000 beneficiaries with lower extremity joint replacement (LEJR) in the Non-BCPI (Bundled Payments for Care Improvement) Markets columns, the means in both the Before BCPI and After BCPI colums should read “0.16.” In the BPCI Markets columns, the means and (SDs) in the Before BCPI column should read “0.15 (0.07)” and in the After BCPI columns, “0.15 (0.06).” The SD for the difference should have read “(−3.7).” In the Market Volume subsection of the Results section, the parenthetical observation about complicated LEJRs in the non-BPCI markets should read “(10 episodes or 0.16 episodes per 1000 beneficiaries …)”; in the BPCI markets, the parenthetical data for complicated LEJRs should read “(17 episodes or 0.15 per 1000 beneficiaries …).” This article was corrected online.

Valley, Thomas S.; Admon, Andrew J.; Zahuranec, Darin B.; Garland, Allan; Fagerlin, Angela; Iwashyna, Theodore J.

Objectives: The distinction between overuse and appropriate use of the ICU hinges on whether a patient would benefit from ICU care. We sought to test 1) whether physicians agree about which types of patients benefit from ICU care and 2) whether estimates of ICU benefit are influenced by factors unrelated to severity of illness. Design: Randomized study. Setting: Online vignettes. Subjects: U.S. critical care physicians. Interventions: Physicians were provided with eight vignettes of hypothetical patients. Each vignette had a single patient or hospital factor randomized across participants (four factors related and four unrelated to severity of illness). Measurements and Main Results: The primary outcome was the estimate of ICU benefit, assessed with a 4-point Likert-type scale. In total, 1,223 of 8,792 physicians volunteered to participate (14% recruitment rate). Physician agreement of ICU benefit was poor (mean intraclass correlation coefficient for each vignette: 0.06; range: 0–0.18). There were no vignettes in which more than two thirds of physicians agreed about the extent to which a patient would benefit from ICU care. Increasing severity of illness resulted in greater estimated benefit of ICU care. Among factors unrelated to severity of illness, physicians felt ICU care was more beneficial when told one ICU bed was available than if ICU bed availability was unmentioned. Physicians felt ICU care was less beneficial when family was present than when family presence was unmentioned. The patient’s age, but not race/ethnicity, also impacted estimates of ICU benefit. Conclusions: Estimates of ICU benefit are widely dissimilar and influenced by factors unrelated to severity of illness, potentially resulting in inconsistent allocation of ICU care. This does not necessarily represent the views of the U.S. Government or the Department of Veterans Affairs. Dr. Valley had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis; conceptualized and designed the study; acquired data; drafted the article; analyzed the statistical data; and obtained the fund. Drs. Valley, Admon, Zahuranec, Garland, Fagerlin, and Iwashyna analyzed and interpreted of data. Drs. Valley, Admon, Zahuranec, Garland, Fagerlin, and Iwashyna critically revised the article for important intellectual content. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by National Institutes of Health T32HL007749 and K23HL140165 (to Dr. Valley) and the Department of Veterans Affairs Health Services Research and Development grant 13–079 (to Dr. Iwashyna). The funding organizations had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the article. Drs. Valley, Zahuranec, and Iwashyna received support for article research from the National Institutes of Health. Dr. Garland’s institution received funding from the Heart and Stroke Foundation of Canada, Research Manitoba, and the Canadian Institutes for Health Research. Drs. Fagerlin and Iwashyna disclosed government work. Dr. Admon disclosed that he does not have any potential conflicts of interest. For information regarding this article, E-mail: valleyt@umich.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Socorro Lupisan, Akira Suzuki, Noel Macalalad, Rutchie Egos, Lydia Sombrero, Michiko Okamoto, Clyde Dapat, Melisa Mondoy, Hazel Galang, Vicente Francisco Froilan Zeta, Flora de la Pena, Vicente Romano, Remigio Olveda, Hitoshi Oshitani

Camille Dussault, Mark P. Nelder, Curtis Russell, Steven Johnson, Linda Vrbova

by Camille Dussault, Mark P. Nelder, Curtis Russell, Steven Johnson, Linda Vrbova Background Aedes japonicus was first documented in Ontario, Canada, in 2001. The objective of this study was to determine the effect of Ae. japonicus establishment on the abundance of other mosquitoes in the Greater Golden Horseshoe (GGH) region of Ontario. Methods Adult mosquito data from the Ontario West Nile virus surveillance program were used. Descriptive analyses, linear trends and distribution maps of average trap count per month for six mosquito species of interest were produced. Multivariable negative binomial regression models were constructed to 1) test whether the invasion of Ae. japonicus affected the abundance of other mosquitoes by comparing the time period before Ae. japonicus was identified in an area (pre-detection), to after it was first identified (detection), and subsequently (establishment), and 2) identify the variables that explain the abundance of the various mosquito species. Results The monthly seasonal average (May–October) of Ae. japonicus per trap night increased from 2002 to 2016, peaking in September, when the average of most other mosquitoes decrease. There were increased numbers of Ae. triseriatus/hendersoni (Odds Ratio (OR): 1.40, 95% Confidence Interval (CI): 1.02–1.94) and decreased numbers of Coquillettidia perturbans (OR: 0.43, 95% CI: 0.26–0.73) in the detection period, compared to the pre-detection period. Additionally, there was a decrease in Cx. pipiens/restuans (OR: 0.87, 95% CI: 0.76–0.99) and Cq. perturbans (OR: 0.68, 95% CI: 0.49–0.94) in the establishment period, compared to the pre-detection period. None of the most parsimonious explanatory models included the period of the establishment of Ae. japonicus. Conclusions There is no evidence that the introduction of Ae. japonicus significantly reduced populations of Ae. triseriatus/hendersoni, Cx. pipiens/restuans or An. punctipennis in the GGH. While further research is needed to understand the impact of the Ae. japonicus invasion on other mosquito species, our work indicates that, on a regional scale, little impact has been noted.…

Raju Sunagar, Sudeep Kumar, Prachi Namjoshi, Sarah J. Rosa, Karsten R. O. Hazlett, Edmund J. Gosselin

by Raju Sunagar, Sudeep Kumar, Prachi Namjoshi, Sarah J. Rosa, Karsten R. O. Hazlett, Edmund J. Gosselin Francisella tularensis (Ft) is a biothreat agent for which there is no FDA-approved human vaccine. Currently, there are substantial efforts underway to develop both vaccines and the tools to assess these vaccines. Tularemia laboratory research has historically relied primarily upon a small number of inbred mouse strains, but the utility of such findings to outbred animals may be limited. Specifically, C57BL/6 mice are more susceptible than BALB/c mice to Ft infection and less easily protected against challenge with highly virulent type A Ft. Thus, depending on the inbred mouse strain used, one could be misled as to which immunogen(s)/vaccine will ultimately be effective in an outbred human population. Accordingly, we evaluated an outbred Swiss Webster (SW) mouse model in direct comparison to a well-established, inbred C57BL/6 mouse model. Mucosal vaccination with the live, attenuated Ft LVS superoxide dismutase (sodB) mutant demonstrated significantly higher protection in outbred SW mice compared to inbred C57BL/6 mice against Ft SchuS4 respiratory challenge. The protection observed in vaccinated outbred mice correlated with lower bacterial density, reduced tissue inflammation, and reduced levels of pro-inflammatory cytokine production. This protection was CD4+ and CD8+ T cell-dependent and characterized by lower titers of serum antibody (Ab) that qualitatively differed from vaccinated inbred mice. Enhanced protection of vaccinated outbred mice correlated with early and robust production of IFN-γ and IL-17A. Neutralizing Ab administered at the time of challenge revealed that IFN-γ was central to this protection, while IL-17A neutralization did not alter bacterial burden or survival. The present study demonstrates the utility of the outbred mouse as an alternative vaccination model for testing tularemia vaccines. Given the limited MHC repertoire in inbred mice, this outbred model is more analogous to the human in terms of immunological diversity.

Laura L. Walkup

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 12, Page 1573-1574, December 15, 2018. …

José Esteban Muñoz-Medina, Miguel Antonio Garcia-Knight, Alejandro Sanchez-Flores, Irma Eloísa Monroy-Muñoz, Ricardo Grande, Joakim Esbjörnsson, Clara Esperanza Santacruz-Tinoco, César Raúl González-Bonilla

by José Esteban Muñoz-Medina, Miguel Antonio Garcia-Knight, Alejandro Sanchez-Flores, Irma Eloísa Monroy-Muñoz, Ricardo Grande, Joakim Esbjörnsson, Clara Esperanza Santacruz-Tinoco, César Raúl González-Bonilla The epidemic potential of Chikungunya virus (CHIKV) was recently made evident by its introduction and rapid expansion in the Caribbean and the Americas. We sought to gain a detailed understanding of the dynamics of the epidemic in Mexico, the country with the highest number of confirmed CHIKV cases in the Americas, and to characterise viral evolution at the population and intra-host level. Analysis of the spatiotemporal distribution of 2,739 diagnosed cases in Mexico from December 2014 to December 2015 showed a rapid nationwide expansion of the epidemic with focalisation in the South West of the country. We sequenced the envelope glycoprotein 1 gene (E1) from 25 patients using the Illumina MiSeq platform and report synonymous and non-synonymous consensus mutations. Bayesian phylogenetic analysis using 249 Asian lineage E1 sequences gave updated estimates of nucleotide substitution rates for E1 and time to most recent common ancestor of major lineages. The analysis indicates phylogenetically-related emergent Latin American clusters in South Western Mexico, Nicaragua and Honduras and transmission of American strains in the Pacific islands. Detailed analysis showed that intra-host changes in E1 mainly occurred in two variable regions (E1:189–220 and E1:349–358) in domains II and III, respectively, in residues involved in inter and intra-envelope spike interactions. At the population level, this study sheds light on the introduction and evolutionary dynamics of CHIKV in the Americas. At the intra-host level, this study identifies mutational hotspots of the E1 protein with implications for understanding the relationship between the CHIKV quasispecies, viral fitness and pathogenesis.

Bach PB, Sachs RE.

In this Viewpoint, the authors review Medicare & Medicaid Services 340B Payment program and recent rules to curtail expansion of drug discounts beyond serving poor patients.

Eby J.

Hospital acquired pneumoniaVentilator associated pneumoniaClinical endpointClinical outcomePatient-reported outcomenon-inferiorityantimicrobial drug development…

Jisun Yoon

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 12, Page 1583-1586, December 15, 2018. …

Meert, Kathleen L.; Guerguerian, Anne-Marie; Barbaro, Ryan; Slomine, Beth S.; Christensen, James R.; Berger, John; Topjian, Alexis; Bembea, Melania; Tabbutt, Sarah; Fink, Ericka L.; Schwartz, Steven M.; Nadkarni, Vinay M.; Telford, Russell; Dean, J. Michael; Moler, Frank W.; for the Therapeutic Hypothermia After Pediatric Cardiac Arrest (THAPCA) Trial Investigators

Objective: To describe neurobehavioral outcomes and investigate factors associated with survival and survival with good neurobehavioral outcome 1 year after in-hospital cardiac arrest for children who received extracorporeal cardiopulmonary resuscitation. Design: Secondary analysis of the Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital trial. Setting: Thirty-seven PICUs in the United States, Canada, and the United Kingdom. Patients: Children (n = 147) resuscitated with extracorporeal cardiopulmonary resuscitation following in-hospital cardiac arrest. Interventions: Neurobehavioral status was assessed using the Vineland Adaptive Behavior Scales, Second Edition, at prearrest baseline and 12 months postarrest. Norms for Vineland Adaptive Behavior Scales, Second Edition, are 100 (mean) ± 15 (SD). Higher scores indicate better functioning. Outcomes included 12-month survival, 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points from baseline, and 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. Measurements and Main Results: Of 147 children receiving extracorporeal cardiopulmonary resuscitation, 125 (85.0%) had a preexisting cardiac condition, 75 (51.0%) were postcardiac surgery, and 84 (57.1%) were less than 1 year old. Duration of chest compressions was greater than 30 minutes for 114 (77.5%). Sixty-one (41.5%) survived to 12 months, 32 (22.1%) survived to 12 months with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points from baseline, and 39 (30.5%) survived to 12 months with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. On multivariable analyses, open-chest cardiac massage was independently associated with greater 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points and greater 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. Higher minimum postarrest lactate and preexisting gastrointestinal conditions were independently associated with lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points and lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. Conclusions: About one third of children survived with good neurobehavioral outcome 1 year after receiving extracorporeal cardiopulmonary resuscitation for in-hospital arrest. Open-chest cardiac massage and minimum postarrest lactate were associated with survival with good neurobehavioral outcome at 1 year. This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or National Institutes of Health. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the National Heart, Lung, and Blood Institute grants HL094345 (to Dr. Moler) and HL094339 (to Dr. Dean). Supported, in part, from the following federal planning grants contributed to the planning of the Therapeutic Hypothermia after Pediatric Cardiac Arrest Trials: HD044955 and HD050531 (to Dr. Moler). Additional, in part, support from the following research networks: Pediatric Emergency Care Applied Research Network from cooperative agreements U03MC00001, U03MC00003, U03MC00006, U03MC00007, and U03MC00008; and the Collaborative Pediatric Critical Care Research Network from cooperative agreements U10HD500009, U10HD050096, U10HD049981, U10HD049945, U10HD049983, U10HD050012, and U01HD049934. Site support from P30HD040677, UL1TR000003UL1, RR 024986, and UL1 TR 000433. Drs. Meert, Guerguerian, Slomine, Berger, Topjian, Fink, and Moler’s institutions received funding from the National Institutes of Health (NIH). Drs. Meert, Guerguerian, Barbaro, Slomine, Christensen, Berger, Topjian, Fink, Schwartz, Telford, Dean, and Moler received support for article research from the NIH. Dr. Barbaro’s institution received funding from National Heart, Lungs, and Blood Institute (NHLBI) grant HL094345, and he disclosed that he is the Extracorporeal Life Support Organization Registry Chair. Dr. Slomine received funding from the American Psychological Association. Drs. Christensen, Schwartz, and Telford’s institutions received funding from the NHLBI. Dr. Berger’s institution also received funding from the Association for Pediatric Pulmonary Hypertension and Actelion. Dr. Schwartz received funding from Novartis AG (consultation regarding serelaxin for treatment of pediatric heart failure; unrelated to the work). Dr. Dean’s institution received funding from the National Institute for Child Health and Human Development. The remaining authors have disclosed that they do not have any potential conflicts of interest. Therapeutic Hypothermia after Pediatric Cardiac Arrest Trial Investigators are listed in the Acknowledgments. For information regarding this article, E-mail: kmeert@med.wayne.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Duscio, Eleonora; Cipulli, Francesco; Vasques, Francesco; Collino, Francesca; Rapetti, Francesca; Romitti, Federica; Behnemann, Tim; Niewenhuys, Julia; Tonetti, Tommaso; Pasticci, Iacopo; Vassalli, Francesco; Reupke, Verena; Moerer, Onnen; Quintel, Michael; Gattinoni, Luciano

Objectives: Minimally invasive extracorporeal CO2 removal is an accepted supportive treatment in chronic obstructive pulmonary disease patients. Conversely, the potential of such technique in treating acute respiratory distress syndrome patients remains to be investigated. The aim of this study was: 1) to quantify membrane lung CO2 removal (VCO2ML) under different conditions and 2) to quantify the natural lung CO2 removal (VCO2NL) and to what extent mechanical ventilation can be reduced while maintaining total expired CO2 (VCO2tot = VCO2ML + VCO2NL) and arterial PCO2 constant. Design: Experimental animal study. Setting: Department of Experimental Animal Medicine, University of Göttingen, Germany. Subjects: Eight healthy pigs (57.7 ± 5 kg). Interventions: The animals were sedated, ventilated, and connected to the artificial lung system (surface 1.8 m2, polymethylpentene membrane, filling volume 125 mL) through a 13F catheter. VCO2ML was measured under different combinations of inflow PCO2 (38.9 ± 3.3, 65 ± 5.7, and 89.9 ± 12.9 mm Hg), extracorporeal blood flow (100, 200, 300, and 400 mL/min), and gas flow (4, 6, and 12 L/min). At each setting, we measured VCO2ML, VCO2NL, lung mechanics, and blood gases. Measurements and Main Results: VCO2ML increased linearly with extracorporeal blood flow and inflow PCO2 but was not affected by gas flow. The outflow PCO2 was similar regardless of inflow PCO2 and extracorporeal blood flow, suggesting that VCO2ML was maximally exploited in each experimental condition. Mechanical ventilation could be reduced by up to 80–90% while maintaining a constant PaCO2. Conclusions: Minimally invasive extracorporeal CO2 removal removes a relevant amount of CO2 thus allowing mechanical ventilation to be significantly reduced depending on extracorporeal blood flow and inflow PCO2. Extracorporeal CO2 removal may provide the physiologic prerequisites for controlling ventilator-induced lung injury. This experiment has been performed at the Department of Experimental Animal Medicine, University of Göttingen, Göttingen, Germany. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by departmental funding. Drs. Eleonora’s, V. Francesco’s, C. Francesca’s, R. Francesca’s, Federica’s, Behnemann’s, Niewenhuys’s, Pasticci’s, Vassalli’s, and Luciano’s institutions received funding from Estor, and they disclosed that Estor (Pero, Milan, Italy) and Dimar (Medolla, Modena, Italy) provided the material for the experiment. Dr. Onnen’s institution received funding from a workshop on hemodynamics supported in part by Pulsion. Dr. Michael’s institution received funding from Estor, and he received funding from Xenios/Fresenius (consultant), Baxter (consultant), Sphere Medical, and Faron (member of the steering committee). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: gattinoniluciano@gmail.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Marco Túlio Aniceto França, Gustavo Saraiva Frio

by Marco Túlio Aniceto França, Gustavo Saraiva Frio Adolescence is a period of transition between childhood and adulthood. The article aims to study the individual, family and school characteristics of adolescents beginning their sexual lives. The database we used was the 2015 PeNSE (National Adolescent School-based Health Survey) and the methodology was the survival analysis. The results show that boys initiate sexual activity before girls and risky behaviors associated with the use of licit and illicit drugs increase the chance of having early sex. In addition, this work highlights the importance of parental practices in reducing the chances of beginning sexual activity, as well as the presence of school workshops on the risks of pregnancy. It should be noted that intervention strategies need to be differentiated according to gender in order to increase effectiveness.

Baselga J.

To the Editor I write to take full responsibility for failing to report appropriate conflict of interest disclosures in articles published in JAMA and the JAMA Network journals between 2015 and 2018, including “Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing,” published in the September 5, 2017, issue of JAMA. In that article, I had reported nothing to disclose. In the interest of full disclosure, I now report the following financial interests and activities that I had been involved in from 2013 to the present, regardless of potential relevance:…

Mette Ø. Agerbæk, Sara Bang-Christensen, Ali Salanti

Malaria research has led to the discovery of oncofetal chondroitin sulfate, which appears to be shared between placental trophoblasts and cancer cells and can be detected by the evolutionary refined malaria protein VAR2CSA. Interestingly, using recombinant VAR2CSA to target oncofetal chondroitin sulfate shows promise for novel cancer diagnostics and therapeutics.

Alfred B. Tiono, Issa Nébié, Nicholas Anagnostou, Aboubacar S. Coulibaly, Georgina Bowyer, Erika Lam, Edith C. Bougouma, Alphonse Ouedraogo, Jean Baptist B. Yaro, Aïssata Barry, Rachel Roberts, Tommy Rampling, Carly Bliss, Susanne Hodgson, Alison Lawrie, Amidou Ouedraogo, Egeruan Babatunde Imoukhuede, Katie J. Ewer, Nicola K. Viebig, Amidou Diarra, Odile Leroy, Philip Bejon, Adrian V. S. Hill, Sodiomon B. Sirima

by Alfred B. Tiono, Issa Nébié, Nicholas Anagnostou, Aboubacar S. Coulibaly, Georgina Bowyer, Erika Lam, Edith C. Bougouma, Alphonse Ouedraogo, Jean Baptist B. Yaro, Aïssata Barry, Rachel Roberts, Tommy Rampling, Carly Bliss, Susanne Hodgson, Alison Lawrie, Amidou Ouedraogo, Egeruan Babatunde Imoukhuede, Katie J. Ewer, Nicola K. Viebig, Amidou Diarra, Odile Leroy, Philip Bejon, Adrian V. S. Hill, Sodiomon B. Sirima Background Heterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63) and Modified Vaccinia Virus Ankara (MVA) vectored vaccines is a strategy previously shown to provide substantial protective efficacy against P. falciparum infection in United Kingdom adult Phase IIa sporozoite challenge studies (approximately 20–25% sterile protection with similar numbers showing clear delay in time to patency), and greater point efficacy in a trial in Kenyan adults. Methodology We conducted the first Phase IIb clinical trial assessing the safety, immunogenicity and efficacy of ChAd63 MVA ME-TRAP in 700 healthy malaria exposed children aged 5–17 months in a highly endemic malaria transmission area of Burkina Faso. Results ChAd63 MVA ME-TRAP was shown to be safe and immunogenic but induced only moderate T cell responses (median 326 SFU/106 PBMC (95% CI 290–387)) many fold lower than in previous trials. No significant efficacy was observed against clinical malaria during the follow up period, with efficacy against the primary endpoint estimate by proportional analysis being 13.8% (95%CI -42.4 to 47.9) at sixth month post MVA ME-TRAP and 3.1% (95%CI -15.0 to 18.3; p = 0.72) by Cox regression. Conclusions This study has confirmed ChAd63 MVA ME-TRAP is a safe and immunogenic vaccine regimen in children and infants with prior exposure to malaria. But no significant protective efficacy was observed in this very highly malaria-endemic setting. Trial registration ClinicalTrials.gov NCT01635647.Pactr.org PACTR201208000404131.…