Ousmane A Koita, Lansana Sangar?, Haiyan D Miller, Aliou Sissako, Moctar Coulibaly, Trevor A Thompson, Sahar? Fongoro, Youssouf Diarra, Mamadou Ba, Ababacar Maiga, Boubakar Diallo, David M Mushatt, Frances J Mather, Jeffrey G Shaffer, Asif H Anwar, Donald J Krogstad

The per-protocol analysis suggested non-inferiority of AQ-13 to artemether plus lumefantrine. By contrast, the intention-to-treat analysis, which included two participants who withdrew and three who were lost to follow-up from the AQ-13 group, did not meet the criterion for non-inferiority of AQ-13, although there were no AQ-13 treatment failures. Studies with more participants (and non-immune participants) are needed to decide whether widespread use of modified 4-aminoquinolones should be recommended.

Nathan C Bahr, Edwin Nuwagira, Emily E Evans, Fiona V Cresswell, Philip V Bystrom, Adolf Byamukama, Sarah C Bridge, Ananta S Bangdiwala, David B Meya, Claudia M Denkinger, Conrad Muzoora, David R Boulware, ASTRO-CM Trial Team

Xpert Ultra detected significantly more tuberculous meningitis than did either Xpert or culture. WHO now recommends the use of Xpert Ultra as the initial diagnostic test for suspected tuberculous meningitis.

G Dennis Shanks, J?rg J M?hrle

In The Lancet Infectious Diseases, Ousmane Koita and colleagues1 reported the results of a randomised, phase 2, non-inferiority clinical trial. They compared AQ-13, a next generation 4-aminoquinoline (4-AQ) compound, with artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in 66 Malian men.

Margaret Khonga, Mark Patrick Nicol

Tuberculous meningitis, a severe manifestation of extra-pulmonary tuberculosis,1,2 has a mortality of more than 60% in HIV-infected people,3 with a 54% risk of chronic neurological complications in those who survive.2 Rapid diagnosis and early initiation of treatment are needed to improve prognosis and minimise debilitating sequelae.2 However, diagnosis is difficult, because cerebrospinal fluid typically contains few Mycobacterium tuberculosis bacilli and large sample volumes cannot always be obtained.

The proliferation of new drug treatments for type 2 diabetes in the United States in the past 15 years, with more than 17 drugs approved in six new classes of antidiabetic drugs, has been promoted by several factors. First, the recognition of the importance of intensive glycemic control to reduce……

Tyler N. Starr

To understand why molecular evolution turned out as it did, we must characterize not only the path that evolution followed across the space of possible molecular sequences but also the many alternative trajectories that could have been taken but were not. A large-scale comparison of real and possible histories would establish whether the outcome of evolution represents an optimal state driven by natural selection or the contingent product of historical chance events; it would also reveal how the underlying distribution of functions across sequence space shaped historical evolution. Here we combine ancestral protein reconstruction with deep mutational scanning to characterize alternative histories in the sequence space around an ancient transcription factor, which evolved a novel biological function through well-characterized mechanisms. We find hundreds of alternative protein sequences that use diverse biochemical mechanisms to perform the derived function at least as well as the historical outcome. These alternatives all require prior permissive substitutions that do not enhance the derived function, but not all require the same permissive changes that occurred during history. We find that if evolution had begun from a different starting point within the network of sequences encoding the ancestral function, outcomes with different genetic and biochemical forms would probably have resulted; this contingency arises from the distribution of functional variants in sequence space and epistasis between residues. Our results illuminate the topology of the vast space of possibilities from which history sampled one path, highlighting how the outcome of evolution depends on a serial chain of compounding chance events.

Leung V, Vincent C, Edens T, et al.

AbstractFecal microbiota transplantation (FMT) may be a novel approach to eliminate multidrug-resistant bacteria from the gut and to prevent future infections. Using whole metagenome sequencing data from eight FMT donor-recipient pairs, we identified 37 and 95 antimicrobial resistance genes that were acquired by or removed from FMT recipients, respectively.

Frencken J, Wittekamp B, Plantinga N, et al.

AbstractBackgroundEnteral and respiratory tract colonization with Gram-negative bacteria may lead to subsequent infections in critically ill patients. We aimed to clarify the interdependence between gut and respiratory tract colonization and their associations with ICU-acquired infections in patients receiving selective digestive tract decontamination (SDD). MethodsColonization status of the rectum and respiratory tract was determined using twice weekly microbiological surveillance in mechanically ventilated subjects receiving SDD between May 2011 and June 2015 in a tertiary medical-surgical ICU in The Netherlands. Acquisition of infections was monitored daily by dedicated observers. Marginal structural models were used to determine the associations between Gram-negative rectal colonization and respiratory tract colonization, ICU-acquired Gram-negative infection, and ICU-acquired Gram-negative bacteremia. ResultsAmong 2,066 ICU admissions, 1,157 (56.0%) ever had documented Gram-negative carriage in the rectum during ICU-stay. Cumulative incidences of ICU-acquired Gram-negative infection and bacteremia were 6.0% (n=124) and 2.1% (n=44), respectively. Rectal colonization was an independent risk factor for both respiratory tract colonization (cause specific hazard ratio (CSHR) 2.93, 95% CI 2.02-4.23) and new Gram-negative infection in the ICU (CSHR 3.04, 95% CI 1.99-4.65). Both rectal and respiratory tract colonization were associated with bacteremia (CSHR 7.37, 95% CI 3.25-16.68 and CSHR 2.56, 95% CI 1.09-6.03, respectively). Similar associations were observed when Enterobacteriaceae and glucose non-fermenting Gram-negative bacteria were analyzed separately.ConclusionsGram-negative rectal colonization tends to be stronger associated with subsequent ICU-acquired Gram-negative infections than Gram-negative respiratory tract colonization. Gram-negative rectal colonization seems hardly associated with subsequent ICU-acquired Gram-negative respiratory tract colonization.

Presentation of Case. Dr. Virginia M. Pierce: A 13-month-old girl was admitted to this hospital because of pneumonia. Nine days before admission, fever and vomiting developed in the child. The vomiting resolved after 2 days, but fever (with a maximum temperature of 39.7?C) continued, and the child……

Liudmila Andreeva

Cytosolic DNA arising from intracellular pathogens triggers a powerful innate immune response. It is sensed by cyclic GMP-AMP synthase (cGAS), which elicits the production of type I interferons by generating the second messenger 2?3?-cyclic-GMP-AMP (cGAMP). Endogenous nuclear or mitochondrial DNA can also be sensed by cGAS under certain conditions, resulting in sterile inflammation. The cGAS dimer binds two DNA ligands shorter than 20 base pairs side-by-side, but 20-base-pair DNA fails to activate cGAS in vivo and is a poor activator in vitro. Here we show that cGAS is activated in a strongly DNA length-dependent manner both in vitro and in human cells. We also show that cGAS dimers form ladder-like networks with DNA, leading to cooperative sensing of DNA length: assembly of the pioneering cGAS dimer between two DNA molecules is ineffective; but, once formed, it prearranges the flanking DNA to promote binding of subsequent cGAS dimers. Remarkably, bacterial and mitochondrial nucleoid proteins HU and mitochondrial transcription factor A (TFAM), as well as high-mobility group box 1 protein (HMGB1), can strongly stimulate long DNA sensing by cGAS. U-turns and bends in DNA induced by these proteins pre-structure DNA to nucleate cGAS dimers. Our results suggest a nucleation-cooperativity-based mechanism for sensitive detection of mitochondrial DNA and pathogen genomes, and identify HMGB/TFAM proteins as DNA-structuring host factors. They provide an explanation for the peculiar cGAS dimer structure and suggest that cGAS preferentially binds incomplete nucleoid-like structures or bent DNA.

Gogtay N, Munshi R, Ashwathnarayan D, et al.

AbstractBackgroundLack of access to rabies immunoglobulin (RIG) contributes to the high rabies mortality. A recombinant human monoclonal antibody (SII RMAb) was tested in a post-exposure prophylaxis (PEP) regimen in comparison to a human RIG (HRIG)-containing PEP regimen.MethodsThis was a Phase 2/3 randomized, single blind, non-inferiority study conducted in 200 participants with WHO category III suspected rabies exposures. On Day 0, participants received either SII RMAb or HRIG (1:1 ratio) into wounds and if required, intramuscularly (IM) along with five doses of rabies vaccine IM on Days 0, 3, 7, 14 and 28. The primary endpoint was the ratio of Day 14 geometric mean concentration (GMC) of RVNA activity as measured by RFFIT for SII RMAb recipients relative to HRIG recipients.Results199 participants received SII RMAb (101) or HRIG (98) and at least one dose of vaccine. The Day 14 GMC ratio of SII RMAb group to HRIG group was 4.23 (96.9018% CI 2.59 - 6.94) with the GMC for SII RMAb recipients of 24.90 IU/mL (95% CI 18.94 - 32.74) and 5.88 IU/mL (95% CI 4.11 - 8.41) for HRIG recipients. Majority of local injection site and systemic adverse reactions reported from both groups were mild to moderate in severity.ConclusionsA PEP regimen containing SII RMAb was safe and demonstrated non-inferiority to HRIG PEP in RVNA production. The novel monoclonal potentially offers a safe and potent alternative for the passive component of PEP and could significantly improve the management of bites from suspected rabid animals.Trial registration numberCTRI/2012/05/002709.

Andreas Hahn, Marc Luetgehetmann, Olfert Landt, Norbert Georg Schwarz, Hagen Frickmann

Objective Enteropathogenic, enterotoxigenic, and enteroaggregative Escherichia coli (EPEC, ETEC, EAEC) are among the most frequent causes of diarrhea during travel or on military deployments. Cost efficient and reliable real-time multiplex PCR (mPCR) assays are desirable for surveillance or point prevalence studies in remote and resource-limited tropical settings. We compared one commercial PCR kit and two in-house assays without using a gold standard to estimate sensitivity and specificity of each assay. Methods Residual materials from nucleic acid extractions of stool samples from two groups with presumably different prevalences and increased likelihood of being infected or colonized by diarrheagenic Escherichia coli were included in the assessment. One group comprised samples from returnees from tropical deployments, the second group was of migrants and study participants from high-endemicity settings. Each sample was assessed with all of the PCR assays. Cycle threshold (Ct) values were descriptively compared. Results The calculated sensitivities for the commercial test versus the in-house tests were for EPEC 0.84 versus 0.89 and 0.96, for ETEC 0.83 versus 0.76 and 0.61, and for EAEC 0.69 versus 0.54 and 0.69. False positive results were rare--specificity was 0.94 and 0.97 for two EPEC tests and 1.0 for all other tests. Most positive samples had late Ct values corresponding to low quantities of pathogens. Discordant test results were associated with late Ct values. Conclusions Since commercial and in-house assays showed comparable results, in-house tests can be assumed to be safe while affording considerable savings, making them a valuable alternative for surveillance testing in resource-limited tropical areas. This article is protected by copyright. All rights reserved.

Minjie Wang, Yuting Wang, Xiaoshuang Feng, Ruijun Wang, Yanmei Wang, Hongmei Zeng, Jun Qi, Hong Zhao, Ni Li, Jianqiang Cai, Chunfeng Qu

Stanisic, D. I., McCarthy, J. S., Good, M. F.

Controlled Human Malaria Infection (CHMI) entails deliberate infection with malaria parasites either by mosquito bite or direct injection of sporozoites or parasitised erythrocytes. When required, the resulting blood-stage infection is curtailed by the administration of anti-malarial drugs. Inducing a malaria infection via inoculation with infected blood was first used as a treatment (malariotherapy) for neurosyphilis in Europe and the United States in the early 1900s. More recently, CHMI has been applied to the fields of malaria vaccine and drug development where it is used to evaluate products in well-controlled early phase proof-of-concept clinical studies thus facilitating progression of only the most promising candidates for further evaluation in malaria-endemic areas. Controlled infections have also been used to immunise against malaria infection. Historically, CHMI studies have been restricted by the need for access to insectaries housing infected mosquitoes or suitable malaria-infected individuals. Evaluation of vaccine and drug candidates has been constrained in these studies by the availability of a limited number of P. falciparum isolates. Recent advances have included cryopreservation of sporozoites, the manufacture of well characterised and genetically distinct cultured malaria cell banks for blood-stage infection, and P. vivax-specific reagents. These advances will help to accelerate malaria vaccine and drug development by making the reagents for CHMI more widely accessible and also enabling a more rigorous evaluation with multiple parasite strains and species. Here we discuss the different applications of CHMI, recent advances in the use of CHMI and ongoing challenges for consideration.

Rudd KE, Delaney A, Finfer S.

Sepsis, most succinctly defined as organ dysfunction due to infection, is estimated to account for more than 5 million deaths around the world each year and to cause or contribute to approximately half of all deaths occurring in hospitals in the United States. A 2016 report from the Healthcare Cost and Utilization Project estimated the cost of treating sepsis in US hospitals in 2013 at $24 billion, making it the most expensive condition treated in US hospitals among all payers. In recent years, the substantial burden of sepsis at the individual, health system, and societal levels has become increasingly recognized by the medical community and the public, culminating in the World Health Organization (WHO) adopting the Improving the Prevention, Diagnosis, and Management of Sepsis resolution at the World Health Assembly in May 2017.

After months of conflicting statements, President Donald Trump has announced that the Deferred Action for Childhood Arrivals (DACA) program, a landmark immigration program introduced during the Obama administration, will be rescinded as of March 2018. The announcement was made in the face of……

Rinaldo Focaccia Siciliano, Bruno Azevedo Randi, Danielle Menosi Gualandro, Roney Orismar Sampaio, M?rcio Sommer Bittencourt, Christian Emmanuel da Silva PelaesRN, Alfredo Jos? Mansur, Pablo Maria Alberto Pomerantzeff, Fl?vio Tarasoutchi, T?nia Mara Varej?o Strabelli

The risk of death from any cause among persons with type 2 diabetes is up to twice that of the general population, and the risk of death from cardiovascular causes is up to four times that of the general population. Improved glycemic control has been shown to improve microvascular outcomes, but a……

The incidence of type 1 diabetes, which currently affects 29 million adults worldwide, is rising. In the United States, the number of patients with type 1 diabetes who are younger than 20 years of age may triple within 30 years. Less than one third of adults with type 1 diabetes achieve a glycated……

Multidrug-resistant tuberculosis (defined by resistance to isoniazid and rifampin) is a consequence of ineffective treatment, both at the individual level, when antibiotics are improperly selected or taken, and at the programmatic level, when the use of standard regimens is based on algorithms that……

Ma M, Wang G, Anderson B, et al.

AbstractBackgroundOur understanding of influenza A virus transmission between humans and pigs is limited.MethodsBeginning in 2015, we used a One Health approach and serial sampling to prospectively study 299 swine workers and 100 controls, their 9000 pigs, and six pig farm environments in China for influenza A viruses (IAVs) using molecular, culture, and immunological techniques. Study subjects were closely monitored for influenza-like illness (ILI) events.Results Upon enrollment, swine workers had higher serum neutralizing antibody titers against swine H1N1 and higher nasal wash total IgA and specific IgA titers against swine H1N1 and H3N2 viruses. Over a period of 12 months, IAVs were detected by qRT-PCR in 46 (11.6%) of 396 environmental swabs, 235 (7.1%) of 3300 pig oral secretion, 23 (5.8%) of 396 water, 20 (5.1%) of 396 aerosol, and 19 (4.8%) of 396 fecal-slurry specimens. Five (15.6%) of 32 subjects with ILI events had nasopharyngeal swab specimens that were positive for IAV and 17 (53.1%) demonstrated 4-fold rises in neutralization titers against a swine virus. Reassorted Eurasian avian-lineage H1N1, pdm09(H1N1)-like, and swine-lineage H3N2 viruses were identified in pig farms. The pdm09(H1N1)-like H1N1 viruses identified in swine were nearly genetically identical to the human H1N1 viruses isolated from the subjects with ILI. ConclusionsThere was considerable evidence of A(H1N1)pdm09-like, swine-lingeage H1N1 and swine-lineage H3N2 viruses circulating, likely reassorting, and likely crossing species within the pig farms. These data suggest that stronger surveillance for novel influenza virus emergence within swine farms is imperative.

Hughes A, Scheer S.

Bobes, R. J., Navarrete-Perea, J., Ochoa-Leyva, A., Anaya, V. H., Hernandez, M., Cervantes-Torres, J., Estrada, K., Sanchez-Lopez, F., Soberon, X., Rosas, G., Maroni Nunes, C., Garcia-Varela, M., Sotelo-Mundo, R. R., Lopez-Zavala, A. A., Gevorkian, G., Acero, G., Laclette, J. P., Fragoso, G., Sciutto, E.

Taenia solium cysticercosis, a parasitic disease that affects human health in various regions of the world, is preventable by vaccination. Both the 97-amino-acid-long KETc7 peptide and its carboxyl-terminal, 18-amino-acid-long sequence (GK-1) are found in Taenia crassiceps. Both peptides, with proven protective capacity against cysticercosis, are part of the highly conserved, cestode-native, 264-amino-acid long protein KE7. KE7 belongs to a ubiquitously distributed family of proteins associated to membrane processes and may participate in several vital cell pathways.This study is aimed to identify the T. solium KE7 (TsKE7) full-length protein and to determine its immunogenic properties. TsKE7 was recombinantly expressed in Escherichia coli Rosetta 2 (rTsKE7) and used to obtain mouse polyclonal antibodies. Anti-rTsKE7 antibodies detected the expected native protein among the 350 spots developed from T. solium cyst vesicular fluid in a mass spectrometry-coupled immune-proteomic analysis. These Abs were then used to screen a phage-displayed 7-random peptide library to map B-cell epitopes. The recognized phages displayed 9 peptides with the consensus motif YF/YPS sequence, which includes YYYPS (named GK-1M for being a GK-1 mimotope), exactly matching a part of GK-1. GK-1M was recognized by 58% of sera from cysticercotic pigs with 100% of specificity, but induced a weak protection against murine cysticercosis.In silico analysis revealed universal T cell epitope(s) in nTsKE7, potentially capable of stimulating CTL and helper T lymphocytes under different MHC class I and class II mouse haplotypes.Altogether, these results provide a rationale for the efficacy of the KETc7, rTsKE7, and GK-1 peptides as vaccines.

Felix L?tsch, Fredrik Waneck, Herbert Auer, Klaus Kaczirek, Georgios Karanikas, Michael Ramharter

M.O Japhet, O Famurewa, M Iturriza- Gomara, O.A Adesina, O.O Opaleye, S Niendorf, C.T Bock, A Mas Marques

Nigeria having approximately 50,000 Rotavirus A (RVA) deaths annually is yet to introduce RVA vaccine into routine national immunization; therefore surveillance of RVA strains circulating before vaccine introduction is essential in evaluating impact of the intervention. Stool samples and sociodemographic data of diarrhoeic children, …

Pennington, L. F., Alouffi, A., Mbanefo, E. C., Ray, D., Heery, D. M., Jardetzky, T. S., Hsieh, M. H., Falcone, F. H.

Urogenital schistosomiasis, caused by the parasitic trematode Schistosoma haematobium, affects over 112 million people worldwide. As with S. mansoni infections, the pathology in urogenital schistosomiasis is mainly related to the egg stage, which induces granulomatous inflammation of affected tissues. Schistosoma eggs and their secretions have been studied extensively for the related S. mansoni organism which is more amenable to laboratory studies. Indeed, we have shown that IPSE/alpha-1 (M-IPSE herein), a major protein secreted from S .mansoni eggs, can infiltrate host cells. Although M-IPSE function is unknown, its ability to translocate to their nucleus and bind DNA suggests a possible role in immune modulation of host cell tissues. Whether IPSE homologs are expressed in other Schistosome species has not been investigated.Here, we describe the cloning of two paralog genes H03-IPSE and H06-IPSE which are the ortholog of M-IPSE, from the egg-cDNA of S. haematobium. Using PCR and immunodetection, we confirmed that expression of these genes is restricted to the egg stage and female adult worms, while H-IPSE protein is only detectable in mature eggs but not adults. We show that both H03-IPSE and H06-IPSE proteins can infiltrate HTB-9 bladder cells when added exogenously to culture medium. Monopartite C-terminal NLS motifs conserved in H03-IPSE ‘SKRRRKY’ and H06-IPSE ‘SKRGRKY’ NLS motifs, are responsible for targeting the proteins to the nucleus of HTB-9 cells, as demonstrated by site directed mutagenesis and GFP tagging. Thus, S. haematobium eggs express IPSE homologs that appear to perform similar functions in infiltrating host cells.

To the Editor: Anderson et al. (June 22 issue) report that head positioning did not influence outcome in patients with acute stroke. The lying-flat position theoretically increases cerebral perfusion, which may alleviate acute ischemia through the recruitment of collaterals. However, in the Head……

A. C. Penn

Long-term potentiation (LTP) of excitatory synaptic transmission has long been considered a cellular correlate for learning and memory. Early LTP (less than 1 h) had initially been explained either by presynaptic increases in glutamate release or by direct modification of postsynaptic AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor function. Compelling models have more recently proposed that synaptic potentiation can occur by the recruitment of additional postsynaptic AMPA receptors (AMPARs), sourced either from an intracellular reserve pool by exocytosis or from nearby extra-synaptic receptors pre-existing on the neuronal surface. However, the exact mechanism through which synapses can rapidly recruit new AMPARs during early LTP remains unknown. In particular, direct evidence for a pivotal role of AMPAR surface diffusion as a trafficking mechanism in synaptic plasticity is still lacking. Here, using AMPAR immobilization approaches, we show that interfering with AMPAR surface diffusion markedly impairs synaptic potentiation of Schaffer collaterals and commissural inputs to the CA1 area of the mouse hippocampus in cultured slices, acute slices and in vivo. Our data also identify distinct contributions of various AMPAR trafficking routes to the temporal profile of synaptic potentiation. In addition, AMPAR immobilization in vivo in the dorsal hippocampus inhibited fear conditioning, indicating that AMPAR diffusion is important for the early phase of contextual learning. Therefore, our results provide a direct demonstration that the recruitment of new receptors to synapses by surface diffusion is a critical mechanism for the expression of LTP and hippocampal learning. Since AMPAR surface diffusion is dictated by weak Brownian forces that are readily perturbed by protein-protein interactions, we anticipate that this fundamental trafficking mechanism will be a key target for modulating synaptic potentiation and learning.

The measurement and reporting of 30-day hospital-readmission rates by the Centers for Medicare and Medicaid Services (CMS) has had a major effect on the delivery of health care. These measures, which were first publicly reported in 2009, were subsequently incorporated into the Hospital Readmissions……

Dinh T, Mushavi A, Shiraishi R, et al.

AbstractBackgroundPreventing mother-to-child human immunodeficiency virus (HIV) transmission (MTCT) depends on early initiation of antiretroviral treatment (ART). We report the 18-month MTCT risk during the transition from Option A to B-plus in Zimbabwe, and assess whether ART pre-conception could eliminate MTCT in breastfeeding populations.MethodsIn 2013,we consecutively recruited a nationally representative sample of 6,051 infants aged 4-12 weeks and their mothers from 151 immunization clinics using a multistage stratified cluster sampling method,. We identified 1,172 HIV-exposed infants (HEIs) and evaluated them at baseline and every three months until the child became HIV-infected, died, or reached age 18 months. ResultsThe cumulative MTCT risk through 18 months post-delivery was 7.0%. Of the HIV-infected mothers, 35.3% started ART pre-conception, 28.9% during pregnancy, 9.7% after delivery, and 16.0% received zidovudine during pregnancy. Compared to mothers without antiretroviral drug use, MTCT among those starting ART pre-conception and during pregnancy were lower by 88% (adjusted hazard ratio [HR] 0.12; 95% confidence interval [0.060.24]) and 75% (adjusted HR 0.25; 0.140.45), respectively. HEIs with birth-weight <2.5kg (LBW) were 2.6-fold more likely to acquire HIV infection compared to those with birth-weight >=2.5kg (adjusted-HR 2.57; 1.444.59). Controlling for other factors, breastfeeding was not significantly associated with MTCT.ConclusionsART pre-conception has the highest impact on reducing MTCT, indicating that HIV-infected, reproductive-age women should be prioritized in "treat-all" strategies. HIV-infected mothers without ART use should be identified at the first immunization visit and treatment initiated to reduce post-delivery MTCT. MTCT risk is higher in mothers with LBW deliveries.

Rhee C, Dantes R, Epstein L, et al.

This cohort study compares estimates of sepsis incidence, outcomes, and trends based on clinical data from US hospital electronic health record systems vs claims-based ICD-9 data.

Suvang Trivedi, Congrong Miao, Mohammad Mousa Al-Abdallat, Aktham Haddadin, Sultan Alqasrawi, Ibrahim Iblan, Mohannad Al Nsour, Tarek Alsanouri, Sami Sheikh Ali, Brian Rha, Susan I. Gerber, Daniel C. Payne, Azaibi Tamin, Natalie J. Thornburg

The Centers for Disease Control and Prevention (CDC) algorithm for detecting presence of serum antibodies against Middle East Respiratory Syndrome coronavirus (MERS-CoV) in subjects with potential infections with the virus has included screening by indirect ELISA against recombinant nucleocapsid (N) protein and confirmation by immunofluorescent staining of infected monolayers and/or microneutralization titration. Other international groups include indirect ELISA assays using the spike (S) protein, as part of their serological determinations. In the current study, we describe development and validation of an indirect MERS-CoV S ELISA to be used as part of our serological determination for evidence of previous exposure to the virus. This article is protected by copyright. All rights reserved …

Simoni Pimenta de Oliveira, Maria Dalva de Barros carvalho, Sandra Marisa Pelloso, Katiany Rizzieri Caleffi-Ferracioli, Vera L?cia Dias Siqueira, Regiane Bertin de Lima scodro, Rosilene Fressatti Cardoso

The detection of the contacts of index cases constitutes an epidemiological and public health strategy for the surveillance and control of TB. The health professionals who promote patient adherence to treatment and the involvement of their families in the fight against TB achieve better results regarding the identification of contacts of index cases, adherence to treatment and cure.

Birgand G, Zahar J, Lucet J.

Multidrug-resistant Enterobacteriaceaeepidemiologytransmissibilitycross-transmissionintensive care units…

Figure 1.

Piroth L, Launay O, Miailhes P, et al.

Kiersten J. Kugeler, Titus Apangu, Joseph D. Forrester, Kevin S. Griffith, Gordian Candini, Janet Abaru, Jimmy F. Okoth, Harriet Apio, Geoffrey Ezama, Robert Okello, Meghan Brett, Paul Mead

Wolf J, Tang L, Flynn P, et al.

AbstractBackgroundInfection is the most important cause of treatment-related morbidity and mortality in pediatric patients treated for acute lymphoblastic leukemia (ALL). Although routine in adults with leukemia, antibacterial prophylaxis is controversial in pediatrics because of insufficient evidence for its efficacy or antibiotic choice and concerns about promoting antibiotic resistance and Clostridium difficile infection.MethodsThis was a single-center, observational cohort study of patients with newly diagnosed ALL, comparing prospectively collected infection-related outcomes in patients who received no prophylaxis, levofloxacin prophylaxis, or other prophylaxis during induction therapy on the total XVI study. A propensity score-weighted logistic regression model was used to adjust for confounders.ResultsOf 344 included patients, 173 received no prophylaxis, 69 received levofloxacin prophylaxis, and 102 received other prophylaxis regimens. Patients receiving prophylaxis had longer duration of neutropenia. Prophylaxis reduced the odds of febrile neutropenia, likely bacterial infection, and bloodstream infection by >=70%. Levofloxacin prophylaxis alone reduced these infections, but it also reduced cephalosporin, aminoglycoside, and vancomycin exposure and reduced the odds of C. difficile infection by >95%. No increase in breakthrough infections with antibiotic-resistant organisms was seen, but this cannot be excluded.ConclusionsThis is the largest study to date of antibacterial prophylaxis during induction therapy for pediatric ALL and the first to include a broad-spectrum fluoroquinolone. Prophylaxis prevented febrile neutropenia and systemic infection. Levofloxacin prophylaxis also minimized the use of treatment antibiotics and drastically reduced C. difficile infection. Although long-term antibiotic-resistance monitoring is needed, these data support using targeted prophylaxis with levofloxacin in children undergoing induction chemotherapy for ALL.

Diro E, Ritmeijer K, Boelaert M, et al.

AbstractBackgroundWe have conducted a single-arm trial evaluating monthly pentamidine secondary prophylaxis (PSP) to prevent visceral leishmaniasis (VL) relapse in Ethiopian HIV-patients. Outcomes at 12 months of PSP have been previously reported, supporting PSP effectiveness and safety. However, remaining relapse-free after PSP discontinuation is vital. We now report outcomes and associated factors for a period of upto 2.5 years after initiating PSP, including one year follow-up after PSP discontinuation.MethodsThe trial had three phases: 1) 12 months (M12) of PSP; 2) a 6-months PSP-extension period if CD4 count

Between 20 and 30% of ischemic strokes are cryptogenic. A strong association between cryptogenic strokes and the presence of patent foramen ovale (PFO) suggests that paradoxical embolism through a PFO may be one important cause of otherwise unexplained infarcts. Percutaneous devices for closure of……

Tariq R, Cho J, Kapoor S, et al.

AbstractBackgroundThe choice of antibiotics for systemic infections in patients with a high risk of Clostridium difficile infection (CDI) remains a clinical practice dilemma. Although some studies suggest that tetracyclines may be associated with a lower risk of CDI than other antibiotics, other results are conflicting. We conducted a systematic review and meta-analysis of studies assessing the risk of CDI with tetracyclines compared with the risk with other antibiotics.MethodsWe conducted a systematic search of MEDLINE, Embase, and Web of Science from January 1978 through December 2016 to include studies assessing the association between tetracycline use and risk of CDI. Weighted summary estimates were calculated using generalized inverse variance with a random-effects model using RevMan 5.3. Study quality was assessed using the Newcastle-Ottawa scale.ResultsSix studies (4 case-control, 2 cohort) with patient recruitment between 1993 and 2012 were included. In the meta-analysis of these studies using the random-effects model, tetracycline use was associated with a decreased risk of CDI (odds ratio, 0.62; 95% CI, 0.47-0.81; P<.001). There was significant heterogeneity among the studies, with an I2 of 53%. No publication bias was seen. Subgroup analysis of studies evaluating the risk of CDI with doxycycline alone also demonstrated a decreased risk of CDI (odds ratio, 0.55; 95% CI, 0.40-0.75; P<.001).ConclusionsMeta-analyses of existing studies suggest that tetracyclines may be associated with a decreased risk of CDI compared with other antimicrobials. It may be reasonable to use tetracyclines whenever appropriate to decrease the burden of future CDI associated with antibiotic use.

Sangdoo Kim

Maternal immune activation (MIA) contributes to behavioural abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring. In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing autism spectrum disorder. In pregnant mice, interleukin-17a (IL-17a) produced by T helper 17 (TH17) cells (CD4+ T helper effector cells involved in multiple inflammatory conditions) induces behavioural and cortical abnormalities in the offspring exposed to MIA. However, it is unclear whether other maternal factors are required to promote MIA-associated phenotypes. Moreover, the underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote TH17 cell differentiation. Pregnant mice that had been colonized with mouse commensal segmented filamentous bacteria or human commensal bacteria that induce intestinal TH17 cells were more likely to produce offspring with MIA-associated abnormalities. We also show that small intestine dendritic cells from pregnant, but not from non-pregnant, females secrete IL-1?, IL-23 and IL-6 and stimulate T cells to produce IL-17a upon exposure to MIA. Overall, our data suggest that defined gut commensal bacteria with a propensity to induce TH17 cells may increase the risk of neurodevelopmental disorders in the offspring of pregnant mothers undergoing immune system activation owing to infections or autoinflammatory syndromes.

Marcel M. M. Kuypers

Bacteria that can oxidize both ammonia to nitrite and nitrite to nitrate seem to be better adapted to ammonia-limited environments than most cultured microbes that oxidize ammonia to nitrite only, contrary to expectations. See Letter p.269…

Abdo A. Elfiky, Wael M. Elshemey

In the year 2015, new Zika virus (ZIKV) broke out in Brazil and spread away in more than 80 countries. Scientists directed their efforts toward viral polymerase in attempt to find inhibitors that might interfere with its function. In this study, molecular dynamics simulation (MDS) was performed over 444 ns for a ZIKV polymerase model. Molecular docking (MD) was then performed every 10 ns during the MDS course to ensure the binding of small molecules to the polymerase over the entire time of the simulation. MD revealed the binding ability of four suggested guanosine inhibitors (GIs); (Guanosine substituted with OH and SH (phenyl) oxidanyl in the 2? carbon of the ribose ring). The GIs were compared to guanosine triphosphate (GTP) and five anti-hepatitis C virus drugs (either approved or under clinical trials). The mode of binding and the binding performance of GIs to ZIKV polymerase were found to be the same as GTP. Hence, these compounds were capable of competing GTP for the active site. Moreover, GIs bound to ZIKV active site more tightly compared to ribavirin, the wide-range antiviral drug.

Moulik S, Chaudhuri S, Sardar B, et al.

AbstractBackgroundThe potential reservoirs of Leishmaniasis in South Asia include relapsed cases of visceral leishmaniasis, patients with Post-Kala-azar dermal leishmaniasis (PKDL) and an asymptomatically infected population. Therefore, assessment of cure in terms of parasite clearance, early detection of PKDL and asymptomatic VL are pivotal for ensuring elimination. This study aimed to monitor the efficacy of Miltefosine and Liposomal Amphotericin B (LAmB) in PKDL based on parasite load.MethodsPatients with PKDL were recruited from the Dermatology outpatient departments or during active field surveys. Skin biopsies were collected at disease presentation, immediately at the end of treatment and six months later. The presence of parasite DNA was assessed by ITS-1 PCR, and quantified by amplification of parasite kDNA.ResultsAt disease presentation (n=184), the median parasite load (IQR) was 5229(896-50898)/?g gDNA. Miltefosine cleared the parasites to <10 in the macular (n=17) and polymorphic (n=21) variant, and remained so up to six months later (<10 parasites). LAmB reduced the parasite burden substantially in macular [n=34, 2128(544-5763)/?g gDNA] and polymorphic PKDL [n=36, 2541(650-9073)/?g gDNA]. Importantly, in patients who returned six months later (n=38), a resurgence of parasites was evident, as the parasites increased to 5665(1840-17067)/?g gDNA.ConclusionsThis study established that quantifying parasite load is an effective approach for monitoring patients with PKDL, wherein Miltefosine demonstrated near total parasite clearance and resolution of symptoms. However, in cases treated with LAmB, the persistence of parasites suggested treatment inadequacy. This needs immediate redressal in view of the Leishmaniasis elimination programme targeted for 2020.

Coussement, Julien; Lebeaux, David; Rouzaud, Claire; Lortholary, Olivier

Purpose of review: Nocardia spp. is a gram-positive bacteria that may cause infections in humans. Nocardiosis has been described since the early years of transplantation. This review aims to provide an overview of present knowledge regarding posttransplant nocardiosis, with a focus on recent findings. Recent findings: Nocardiosis is not rare among transplant recipients, especially after thoracic transplantation and/or in case of intense immunosuppressive regimen or use of tacrolimus. Low-dose cotrimoxazole is not effective to prevent nocardiosis. Although lung is the most common site of infection, more than 40% of organ transplant patients have a disseminated infection. As central nervous system involvement is frequent (about 1/3 of the patients) and possibly asymptomatic, brain imaging is mandatory. Diagnosis relies on direct examination and culture; molecular species identification is useful to guide treatment. Although cotrimoxazole is the drug for which we have the strongest clinical experience, other antibiotics such as linezolid, parenteral cephalosporins, carbapenems, and amikacin can be used to treat nocardiosis. Although treatment duration has historically been set to at least 6 months, shorter durations (…

Michael Coates

Polypterid fish were considered to be archaic outliers of the bony-fish grouping. Fossil analysis now places them at the heart of early ray-finned fishes, a radical change that transforms the timing of their evolution. See Letter p.265…

Case-control studies have shown an association between patent foramen ovale (PFO) and cryptogenic stroke, particularly among patients younger than 55 years of age and among patients with an associated atrial septal aneurysm or a substantial right-to-left interatrial shunt. The role of closure of……