Patent foramen ovale (PFO) is a potential cause of cryptogenic stroke. Three previous randomized trials of transcatheter PFO closure did not show a lower risk of recurrent stroke with PFO closure than with medical therapy in their primary intention-to-treat analyses; however, secondary analyses……

Wu J, Yang S, Cao Q, et al.

AbstractBackgroundPneumonia is now the second leading cause of death for children aged <5 years worldwide. However, analyses of the long-term evolution of under-5 mortality from pneumonia are still scarce in the literature. We aimed to explore long-term trends of under-5 mortality from pneumonia in 56 countries from 1960 to 2012.MethodsData on under-5 mortality from pneumonia were extracted from the World Health Organization mortality database. Long-term trends were assessed for 56 countries and for 4 national income transition groups. We also used joinpoint regression analysis to detect distinct period segments of long-term trends and estimate the annual percent of changes of each period segment.ResultsThe average mortality rate from pneumonia for children aged 0-4 years in 56 countries declined from 163.0 per 100000 children (95% confidence interval [CI], 119.4 to 212.8) in 1960 to 9.9 per 100000 children (95% CI, 6.4 to 13.4) in 2012, with an average annual percent of change of -5.6% (95% CI, -7.2% to -3.9%). The temporal trends of childhood mortality were different between national income transition groups.ConclusionsOur findings suggest a striking overall downward trend in under-5 mortality from pneumonia between 1960 and 2012. However, the rate and absolute terms of decline differ by national income transition group. These variable patterns between national income transition groups may inform further intervention setting and priority setting.

Claudio Ucciferri, Manuela Tamburro, Katia Falasca, Michela Lucia Sammarco, Giancarlo Ripabelli, Jacopo Vecchiet

Aims of the study were to evaluate Human Papillomavirus (HPV) and type-specific prevalence in four anatomical sites in HIV infected men who have sex with men (MSM) compared with HIV uninfected MSM. Participants were recruited among the attendees of Infectious Diseases Clinics in Central Italy. A trained medical practitioner collected by interview sociodemographic data and information on medical history, sexual behavior and drug use. Swabs from anal canal, oral cavity, urethral mucosa and coronal sulcus were tested for HPV DNA and genotyping. Ninety MSM were enrolled, 45 subjects within each group. Overall, 48.9% MSM were HPV positive and prevalence was higher in HIV infected men (60% vs 37.8%, P = 0.035). HPV at multiple anatomic sites occurred in 59.1% MSM, with 34.1% and 22.7% at two and three sites respectively. Prevalence of anal, coronal sulcus, oral and urethral HPV was 96.3%, 37%, 21.6% and 18.5% in HIV infected MSM, and 70.6%, 70.6%, 29.4% and 23.5% among HIV uninfected. A similar proportion of HIV infected and uninfected MSM (59.2% and 58.8%) carried at least one high-risk genotype. Prevalence of types covered by nonavalent vaccine was 77.8% in HIV infected compared with 82.3% in HIV uninfected MSM. HPV 58 and 16 were mostly detected in HIV positive (43.7% and 31.2%) and negative MSM (50% and 40%). HPV detection rate underlined the high vulnerability of MSM to acquire multisite infections, characterized by various genotype combinations. Since nonavalent vaccine could have prevented 80% of HPV infections, study findings support the implementation of vaccination programs among MSM. This article is protected by copyright. All rights reserved …

Kevin T. Beier

Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations.

Piantadosi A, Kanjilal S, Ganesh V, et al.

AbstractWe describe a patient with severe and progressive encephalitis of unknown etiology. We performed rapid metagenomic sequencing from cerebrospinal fluid and identified Powassan virus, an emerging tick-borne flavivirus that has been increasingly detected in the United States.

Bouzid, F., Bregeon, F., Lepidi, H., Donoghue, H. D., Minnikin, D. E., Drancourt, M.

Mycobacterium canettii, with smooth colony morphology, is the tuberculous organism retaining most genetic traits from the putative last common ancestor of the rough morphology Mycobacterium tuberculosis complex. To explore whether M. canettii can infect individuals by the oral route, mice were fed with phosphate buffered saline or 106 M. canettii and were sacrificed over a 28-day experiment. While no M. canettii was detected in negative controls, M. canettii-infected mice yielded granuloma-like lesions in 4/4 lungs at days 14 and 28 post-inoculation (p.i.), positive PCR detection of M. canettii in 5/8 mesenteric lymph nodes at days 1 and 3 p.i., also in 5/6 pooled stools collected from day 1 to day 28 p.i. Smooth M. canettii-colonies grew from 68% of lungs and 36% of spleens and cervical lymph nodes but in less than 20% of axillary lymph nodes, liver, brown fat, kidney or blood throughout the 28-day experiment. Ready murine translocation after digestive tract challenge demonstrates the potential of ingested M. canettii to relocate to distant organs and lungs. The demonstration of this relocation supports the possibility that populations could be infected by environmental M. canettii.

It is estimated that 470,000 patients receive radiotherapy each year in the United States. As many as half of patients with cancer will receive radiotherapy. Improvements in diagnosis, therapy, and supportive care have led to increasing numbers of cancer survivors. In response, the emphasis of……

Yeong Shin Yim

Viral infection during pregnancy is correlated with increased frequency of neurodevelopmental disorders, and this is studied in mice prenatally subjected to maternal immune activation (MIA). We previously showed that maternal T helper 17 cells promote the development of cortical and behavioural abnormalities in MIA-affected offspring. Here we show that cortical abnormalities are preferentially localized to a region encompassing the dysgranular zone of the primary somatosensory cortex (S1DZ). Moreover, activation of pyramidal neurons in this cortical region was sufficient to induce MIA-associated behavioural phenotypes in wild-type animals, whereas reduction in neural activity rescued the behavioural abnormalities in MIA-affected offspring. Sociability and repetitive behavioural phenotypes could be selectively modulated according to the efferent targets of S1DZ. Our work identifies a cortical region primarily, if not exclusively, centred on the S1DZ as the major node of a neural network that mediates behavioural abnormalities observed in offspring exposed to maternal inflammation.

Nobuhiko Ogasawara, Masahiro Kobayashi, Norio Akuta, Yoko Kominami, Shunichiro Fujiyama, Yusuke Kawamura, Hitomi Sezaki, Tetsuya Hosaka, Fumitaka Suzuki, Satoshi Saitoh, Yoshiyuki Suzuki, Yasuji Arase, Kenji Ikeda, Mariko Kobayashi, Hiromitsu Kumada

Little information is available on the impact of direct-acting antiviral (DAA) therapy on changes in liver fibrosis and steatosis. Liver stiffness (LS) and controlled attenuation parameter (CAP) values were evaluated using transient elastography. The study subjects were 214 elderly patients infected with HCV genotype 1b who received 24-week daclatasvir and asunaprevir dual therapy. All patients of this retrospective study had no hepatocellular carcinoma before and during DAA therapy. LS and CAP were assessed before treatment (baseline), at end of treatment (EOT), and at 24, 48, 72 weeks (W) after EOT. The rate of sustained viral response (SVR) by daclatasvir and asunaprevir therapy was 91%. LS values for the entire group correlated with Fib-4 index at baseline (r=0.565, p<0.001). LS in both chronic hepatitis group (Fib-4 index …

Ehsan Mostafavi, Behzad Pourhossein, Saber Esmaeili, Fahimeh Bagheri Amiri, Sahar Khakifirouz, Nariman Shah-hosseini, Seyed Mehdi Tabatabaei

Cosme Alvarado-Esquivel, Luis Francisco S?nchez-Anguiano, Jes?s Hern?ndez-Tinoco, ?ngel Osvaldo Alvarado-F?lix

No information about hepatitis E virus (HEV) infection in pigs in the northern Mexican state of Durango exists. We determined the seroprevalence and correlates of anti-HEV IgG antibodies in pigs in Durango, Mexico. Through a cross-sectional study, we studied 427 pigs raised in backyards (n = 328), or slaughtered (n = 99) in Durango. Sera of pigs were analyzed for anti-HEV IgG antibodies using a commercially available enzyme-linked immunoassay. Antibodies to HEV were found in 193 (45.2%) of the 427 pigs studied. A significantly higher seroprevalence was observed in slaughtered pigs (79.8%) than in backyard pigs (34.8%). Bivariate analysis showed that HEV seropositivity was associated with age, sex, breed, climate, altitude, mean annual temperature, mean annual rainfall and farm raising. Logistic regression analysis showed that HEV seropositivity was associated with the origin (Sonora State) of pigs (OR =6.51; 95% CI: 3.74-11.32; P …

Job Dekker

The 4D Nucleome Network aims to develop and apply approaches to map the structure and dynamics of the human and mouse genomes in space and time with the goal of gaining deeper mechanistic insights into how the nucleus is organized and functions. The project will develop and benchmark experimental and computational approaches for measuring genome conformation and nuclear organization, and investigate how these contribute to gene regulation and other genome functions. Validated experimental technologies will be combined with biophysical approaches to generate quantitative models of spatial genome organization in different biological states, both in cell populations and in single cells.

Guo-Qiang Zhang

Constituting approximately 10% of flowering plant species, orchids (Orchidaceae) display unique flower morphologies, possess an extraordinary diversity in lifestyle, and have successfully colonized almost every habitat on Earth. Here we report the draft genome sequence of Apostasia shenzhenica, a representative of one of two genera that form a sister lineage to the rest of the Orchidaceae, providing a reference for inferring the genome content and structure of the most recent common ancestor of all extant orchids and improving our understanding of their origins and evolution. In addition, we present transcriptome data for representatives of Vanilloideae, Cypripedioideae and Orchidoideae, and novel third-generation genome data for two species of Epidendroideae, covering all five orchid subfamilies. A. shenzhenica shows clear evidence of a whole-genome duplication, which is shared by all orchids and occurred shortly before their divergence. Comparisons between A. shenzhenica and other orchids and angiosperms also permitted the reconstruction of an ancestral orchid gene toolkit. We identify new gene families, gene family expansions and contractions, and changes within MADS-box gene classes, which control a diverse suite of developmental processes, during orchid evolution. This study sheds new light on the genetic mechanisms underpinning key orchid innovations, including the development of the labellum and gynostemium, pollinia, and seeds without endosperm, as well as the evolution of epiphytism; reveals relationships between the Orchidaceae subfamilies; and helps clarify the evolutionary history of orchids within the angiosperms.

Basil J. Greber

Human transcription factor IIH (TFIIH) is part of the general transcriptional machinery required by RNA polymerase II for the initiation of eukaryotic gene transcription. Composed of ten subunits that add up to a molecular mass of about 500 kDa, TFIIH is also essential for nucleotide excision repair. The seven-subunit TFIIH core complex formed by XPB, XPD, p62, p52, p44, p34, and p8 is competent for DNA repair, while the CDK-activating kinase subcomplex, which includes the kinase activity of CDK7 as well as the cyclin H and MAT1 subunits, is additionally required for transcription initiation. Mutations in the TFIIH subunits XPB, XPD, and p8 lead to severe premature ageing and cancer propensity in the genetic diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, highlighting the importance of TFIIH for cellular physiology. Here we present the cryo-electron microscopy structure of human TFIIH at 4.4 ? resolution. The structure reveals the molecular architecture of the TFIIH core complex, the detailed structures of its constituent XPB and XPD ATPases, and how the core and kinase subcomplexes of TFIIH are connected. Additionally, our structure provides insight into the conformational dynamics of TFIIH and the regulation of its activity.

John J, Giri S, Karthikeyan A, et al.

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>In 2014, 2 studies showed that inactivated poliovirus vaccine (IPV) boosts intestinal immunity in children previously immunized with oral poliovirus vaccine (OPV). As a result, IPV was introduced in mass campaigns to help achieve polio eradication.<div class="boxTitle">Methods.</div>We conducted an open-label, randomized, controlled trial to assess the duration of the boost in intestinal immunity following a dose of IPV given to OPV-immunized children. Nine hundred healthy children in Vellore, India, aged 1-4 years were randomized (1:1:1) to receive IPV at 5 months (arm A), at enrollment (arm B), or no vaccine (arm C). The primary outcome was poliovirus shedding in stool 7 days after bivalent OPV challenge at 11 months. <div class="boxTitle">Results.</div>For children in arms A, B, and C, 284 (94.7%), 297 (99.0%), and 296 (98.7%), respectively, were eligible for primary per-protocol analysis. Poliovirus shedding 7 days after challenge was less prevalent in arms A and B compared with C (24.6%, 25.6%, and 36.4%, respectively; risk ratio 0.68 [95% confidence interval: 0.53-0.87] for A versus C, and 0.70 [0.55-0.90] for B versus C).<div class="boxTitle">Conclusions.</div>Protection against poliovirus remained elevated 6 and 11 months after an IPV boost, although at a lower level than reported at 1 month.<div class="boxTitle">Clinical Trials Registration.</div>CTRI/2014/09/004979.</span>…

Antonia Wallrapp

Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU-NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces.

Gurieva T, Dautzenberg M, Gniadkowski M, et al.

AbstractBackgroundThe global emergence of infections caused by Enterobacteriaceae resistant to expanded-spectrum cephalosporins (ESCs) in intensive care units (ICUs) is, at least partly, driven by cross-transmission. Yet, individual transmission capacities of bacterial species have not been quantified.MethodsIn this post-hoc analysis of a multicenter study in 13 European ICUs prospective surveillance data and a mathematical model were used to estimate transmission capacities and single admission reproduction numbers (RA) of Escherichia coli and non-E. coli Enterobacteriaceae, all being ESC-resistant. Surveillance was based on a chromogenic selective medium for ESC-resistant Enterobacteriaceae, allowing identification of E. coli and of Klebsiella, Enterobacter, Serratia, Citrobacter species, grouped as non-E. coli Enterobacteriacea (non-EcE).ResultsAmong 11,420 patients included, the admission prevalence was 3.8% for non-EcE (74% being Klebsiella pneumoniae) and 3.3% for E. coli. Acquisition rates were 7.4 and 2.6 per 100 admissions at risk for non-EcE and E. coli, respectively. The estimated transmission capacity of non-EcE was 3.7 (95% credibility interval 1.4-11.3) times higher than of E. coli, yielding single admission reproduction numbers (RA) of 0.17 (95% credibility interval 0.094-0.29) for non-EcE and 0.047 (0.018-0.098) for E. coli.ConclusionsIn ICUs non-EcE, mainly being K. pneumoniae, are 3.7 times more transmissible than E.coli. Estimated RA values of these bacteria were below the critical threshold of one, suggesting that in these ICUs outbreaks typically remain small with current infection control policies.

On the basis of what I had read previously in the Journal, I recently explained to my 44-year-old patient that closing his patent foramen ovale (PFO) after his stroke was not advisable. How can we now have three trials showing that closure prevents recurrent stroke, given that in the past 5 years,……

To the Editor: Goldberg et al. (June 15 issue) report cure of hepatitis C virus (HCV) infection, after transplantation of kidneys infected with HCV (genotype 1) into HCV-negative recipients, with the use of a 12-week course of elbasvir-grazoprevir. However, data on other types of solid-organ……

To the Editor: Recent outbreaks of illnesses that may be prevented by vaccines have increased public debate about vaccination behaviors (i.e. whether or not and when parents choose to vaccinate a child), and California has been a key affected state. One reason that parents choose not to have their……

Disorders of brain function are leading causes of disease burden. The clinical manifestations of neurologic and psychiatric disorders are often caused by malfunction in circuits in the brain that regulate sensory, motor, cognitive, and behavioral functions. The signs and symptoms of the disorders……