Maxime J M van der Valk, Denise E Hilling, Esther Bastiaannet, Elma Meershoek-Klein Kranenbarg, Geerard L Beets, Nuno L Figueiredo, Angelita Habr-Gama, Rodrigo O Perez, Andrew G Renehan, Cornelis J H van de Velde, IWWD Consortium

This dataset has the largest series of patients with rectal cancer treated with a W&W approach, consisting of approximately 50% data from previous cohort series and 50% unpublished data. Local regrowth occurs mostly in the first 2 years and in the bowel wall, emphasising the importance of endoscopic surveillance to ensure the option of deferred curative surgery. Local unsalvageable disease after W&W was rare.

Dipen J Parekh, Isildinha M Reis, Erik P Castle, Mark L Gonzalgo, Michael E Woods, Robert S Svatek, Alon Z Weizer, Badrinath R Konety, Mathew Tollefson, Tracey L Krupski, Norm D Smith, Ahmad Shabsigh, Daniel A Barocas, Marcus L Quek, Atreya Dash, Adam S Kibel, Lynn Shemanski, Raj S Pruthi, Jeffrey Scott Montgomery, Christopher J Weight, David S Sharp, Sam S Chang, Michael S Cookson, Gopal N Gupta, Alex Gorbonos, Edward M Uchio, Eila Skinner, Vivek Venkatramani, Nachiketh Soodana-Prakash, Kerri Kendrick, Jos

In patients with bladder cancer, robotic cystectomy was non-inferior to open cystectomy for 2-year progression-free survival. Increased adoption of robotic surgery in clinical practice should lead to future randomised trials to assess the true value of this surgical approach in patients with other cancer types.

Sumathi Sivapalasingam, Mohamed Kamal, Rabih Slim, Romana Hosain, Weiping Shao, Randall Stoltz, Joseph Yen, Laura G Pologe, Yuan Cao, Michael Partridge, Giane Sumner, Leah Lipsich

REGN3470-3471-3479 was well tolerated, displayed linear pharmacokinetics, and did not lead to detectable immunogenicity. These data support further clinical development of REGN3470-3471-3479 as a single-dose therapeutic drug for acute Ebola virus infection.

Christian Kraef, Jonas Arand, Luzia Veletzky, Hansjoerg Schäfer, Sabine Jordan, Stefan Schmiedel, Michael Ramharter

A 17-year-old German student with acute abdominal pain attended a regional hospital in northern Germany. During interview, he said that 2 weeks earlier his ejaculate had changed to a yellowish brown colour. Laboratory analysis showed leucocytosis (21·9 × 109 per L) with a marked eosinophilia (78%, 15·3 × 109 per L) and slightly elevated liver enzymes (alanine aminotransferase 101 U/L). An acute appendicitis was suspected and laparoscopic appendectomy was performed.

The Lancet

The 11th version of the International Classification of Diseases (ICD) launched on June 18 is the latest attempt at systematically describing and categorising all human mortality and morbidity. Designed for the global digital age, it is an onscreen, multipurpose, multilingual database interconnecting with other operating systems—including electronic hospital records. It is a quantum leap forward from the ICD-10, which, although revised several times over the past two decades, was originally published in 1992, when internet use was minimal, smartphones were unheard of, and patient records were paper based.

The Lancet Respiratory Medicine

In 1951, The Lancet published a trial of the (then) new drug aminophylline (theophylline plus ethylenediamine) in 12 patients with emphysema and 12 healthy participants. The investigators found no important change in lung volume or spirometry in the patients 30 minutes after treatment. Despite this early negative result, theophylline has been a treatment for chronic obstructive pulmonary disease (COPD) for around 70 years. Although it has gained and lost popularity during that time, it maintains a place in COPD guidelines (albeit in limited circumstances) to this day.

Claire McBrien, Anand Devaraj, Andrew G Nicholson, Andrew Menzies-Gow

When does difficult asthma represent more than asthma that is difficult to manage? This case might seem typical of severe asthma at first glance, but the clinical features and abnormal test results highlight the need to keep an open mind regarding possible alternative diagnoses. Test your clinical acumen and learn about this atypical presentation of an important condition that was investigated and managed at the Royal Brompton Hospital.

Mark Honigsbaum

“The brevity of the influenza pandemic of August–September 1918 posed great problems to doctors at the time… It has posed great problems to historians ever since.”Terence Ranger…

Amanda McClelland, Thomas R Frieden

Public health was born from crises. Before the influenza pandemic of 1918, many diseases were seen as something that mostly affected the poor, to be blamed on those who had not pulled themselves out of poverty. The 1918 influenza pandemic is estimated to have killed up to 50 million people, infecting rich and poor alike. Viruses were just beginning to be recognised, and doctors had no vaccines, no antivirals, no antibiotics. The pandemic revealed that disease is a population-wide issue, not simply an individual burden.

John S Oxford, Douglas Gill

The influenza epidemic of 1918 represented the greatest failure of medical science in the 20th century. Fortunately, research throughout subsequent years has been making amends. Some studies have applied RT-PCR to the tissue samples from that time, whereas others have reconstructed the pathogen in its virulent state. But the resurrection of the 1918 influenza virus leaves questions unanswered: although more virulent than contemporary H1N1 epidemic viruses in animal models, this increased virulence of the 1918 influenza virus is not sufficient to have been the sole cause of the high mortality rates recorded in humans during the epidemic.

Michele Augusto Riva, Michael Belingheri, Giancarlo Cesana

In Europe, the incidence of tuberculosis increased progressively after the Middle Ages, peaking between the eighteenth and nineteenth century. The spread of tuberculosis in historical populations is generally studied by analysing the frequency of tuberculosis-related skeletal lesions in human remains. These studies are usually based on the remains of people buried in cemeteries and mass graves, so the epidemiology of tuberculosis among the upper-classes, who were generally buried in private chapels and churches, has rarely been investigated.

Paul Webster

The development of drugs to cure hepatitis C opens the door to using infected organs for donation. Paul Webster reports.

Nicola Kavanagh, Fergal J. O’Brien, Steve W. Kerrigan

by Nicola Kavanagh, Fergal J. O’Brien, Steve W. Kerrigan Osteomyelitis is an inflammatory bone infection that is caused most commonly by the opportunistic pathogen Staphylococcus aureus. Research into staphylococcal induced bone infection is typically conducted using traditional 2D in vitro culture settings, which is not fully representative of the dynamic in vivo environment. In this study we utilised a collagen glycosaminoglycan scaffold, previously developed for bone tissue engineering, as a representative 3D model of infection. The scaffold resisted degradation and retained its pore structure, which is important for cellular function and survival, when seeded with both cells and bacteria. Using this model, we showed that in the presence of S. aureus, osteoblast proliferation was reduced over 21 days. Interestingly however these cells were more metabolically active compared to the uninfected cells and demonstrated increased mineralisation. Protein A (SpA) is a virulence factor found on the surface of S. aureus and has been shown to interact with osteoblasts. When SpA was removed from the surface of S. aureus, the osteoblasts show comparable activity with the uninfected cells—demonstrating the importance of SpA in the interaction between bone cells and S. aureus. Our results suggest that infected osteoblasts are capable of over-compensating for bone loss and bone destruction by increasing mineralisation in a 3D environment, key elements required for ensuring bone strength. It also reinforces our previously established result that S. aureus SpA is a critical mediator in osteomyelitis and might be a potential novel drug target to treat osteomyelitis by preventing the interaction between S. aureus and osteoblasts.

Jon Cohen, Gustavo Lopardo, Waldo H. Belloso, Britta Lassmann

Abstract Introduction The emergence of carbapenemase-producing Klebsiella pneumonia (KPC-Kp) has become a significant problem in terms of public health and clinical outcome in many hospitals in Southern Europe. Treatment options are usually limited and effective treatment of infections caused by these pathogens is a considerable challenge for clinicians. Ceftazidime–avibactam has been recently approved for the treatment of difficult-to-treat infections due to aerobic Gram-negative organisms in patients with limited treatment options. Case report We reported the first case of KPC-Kp septic thrombophlebitis and right atrial endocarditis associated with metastatic lung abscesses successfully treated with a prolonged ceftazidime/avibactam plus ertapenem treatment course, suggesting that this combination therapy could be safe and effective for serious Gram-negative infections. Interestingly, we also observed an apparent discrepancy between clinical and microbiological courses: the patient became rapidly afebrile; hemodynamically stable and his procalcitonin levels showed a prompt decreasing trend. Nevertheless, blood cultures remained persistently positive for a prolonged period. Conclusion In conclusion, ceftazidime–avibactam plus ertapenem was a safe and effective therapy of serious endovascular infection due to KPC-Kp. Moreover, in this setting, follow-up blood cultures might represent an irreplaceable tool to guide the therapy.

Abstract Background Plasmodium falciparum malaria is an important cause of morbidity in northern Uganda. This study was undertaken to assess village-, household-, and individual-level risk factors of asymptomatic falciparum malaria in children in 12 villages in northern Uganda. Methods Between 10/2011 and 02/2014, 1006 apparently healthy children under 16 years old were enrolled in 12 villages using a stratified, multi-stage, cluster survey design and assessed for P. falciparum malaria infection using the rapid diagnostic test (RDT) and thick film microscopy (TFM), and structured interviewer-administered questionnaires. Associations between weighted P. falciparum malaria prevalence (pfPR), based on RDT, and covariates were estimated as odds ratios and 95% confidence intervals (ORs, 95% CIs) using logistic models accounting for the survey design. Results Among 942 (93.5%) children successfully tested, pfPR was 52.4% by RDT and 32.7% by TFM. Overall pfPR was lower in villages where indoor residual insecticide spray (IRS) was, versus not, implemented (18.4% versus 75.2%, P 

Chou, S., Satterwhite, L. E., Ercolani, R. J.

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor recently approved as prophylaxis in stem cell transplant recipients. In further studies of emerging drug resistance, a baseline laboratory CMV strain was serially propagated in cell culture under a combination of letermovir and ganciclovir. In 8 experiments, UL56 terminase gene mutations were detected beginning at 10 passages, including novel amino acid substitutions V236A, L328V and A365S, in a region previously associated with letermovir resistance. Outside this region, UL56 substitution C25F was detected at moderate drug concentrations in 2 experiments, as either the first detected mutation, or adding to a preexisting substitution V231L. In all cases, mutation at UL56 codon 325 conferring absolute letermovir resistance eventually developed at a median of 20 passages. No UL97 kinase or UL54 DNA polymerase mutations relevant to ganciclovir resistance were detected until many passages after the first detection of UL56 mutations. UL56 substitutions V236A, L328V and A365S were shown to confer borderline or low-grade letermovir resistance, while C25F conferred 5.4-fold increased letermovir resistance (EC50) by itself and 46-fold in combination with V231L. The evolution of resistance mutations sooner in UL56 than in UL54 or UL97 is consistent with prior in vitro observations, and UL56 codon 25 is a genetic locus for letermovir resistance distinct from those previously described.

Abstract Background Hepatitis C (HCV) diagnosis and care is a major challenge for people who use illicit drugs, and is characterised by low rates of testing and treatment engagement globally. New approaches to fostering engagement are needed. We explored the acceptability of remote forms of HCV testing including self-testing and self-sampling among people who use drugs in London, UK. Methods A qualitative rapid assessment was undertaken with people who use drugs and stakeholders in London, UK. Focus groups were held with men who have sex with men engaged in drug use, people who currently inject drugs and people who formerly injected drugs (22 participants across the 3 focus groups). Stakeholders participated in semi-structured interviews (n = 5). We used a thematic analysis to report significant themes in participants’ responses. Results We report an overarching theme of ‘tension’ in how participants responded to the acceptability of remote testing. This tension is evident across four separate sub-themes we explore. First, choice and control, with some valuing the autonomy and privacy remote testing could support. Second, the ease of use of self testing linked to its immediate result and saliva sample was preferred over the delayed result from a self administered blood sample tested in a laboratory. Third, many respondents described the need to embed remote testing within a supportive care pathway. Fourth, were concerns over managing a positive result, and its different meanings, in isolation. Conclusions The concept of remote HCV testing is acceptable to some people who use drugs in London, although tensions with lived experience of drug use and health system access limit its relevance. Future development of remote testing must respond to concerns raised in order for acceptable implementation to take place.

Abstract Background The burden of mother-to-child transmission rate of HIV is high and risk factors are common in Ethiopia. This systematic review and meta-analysis intended to provide the pooled estimation of mother-to-child transmission rate and its risk factors in Ethiopia. Methods We searched PubMed, Google Scholar, EMBASE and Web of Science electronic databases for all available references. We included observational studies including case-control, cohort, and cross-sectional studies. The search was further limited to studies conducted in Ethiopia and publish in English. Heterogeneity was checked using the I2 statistic. Egger’s test and the funnel plot were used to assess publication bias. A meta-analysis using a weighted inverse variance random-effects model was performed. Results A total of 18 studies with 6253 individuals were included in this systematic review and meta-analysis. Of these, 14 studies with 4624 individuals were used to estimate the prevalence. The estimated pooled prevalence of mother-to-child transmission of HIV was 11.4% (95% CI = 9.1–13.7). The pooled adjusted odds ratio (AOR) of mother-to-child transmission of HIV for the infants from rural area was 3.8 (95% CI = 1.4 to 6.3), infants delivered at home was 3.2 (95% CI = 1.2 to 5.2), infant didn’t take antiretroviral prophylaxis was 5.8 (95% CI = 1.5 to 10.3), mother didn’t take antiretroviral prophylaxis was 6.1 (95% CI = 2.5 to 9.6), mothers didn’t receive PMTCT intervention was 5.1 (95% CI = 1.6, 8.6), and on mixed feeding was 4.3 (95% CI = 1.8 to 6.7). Conclusions This systematic review and meta-analysis showed that mother-to-child transmission rate of HIV was high in Ethiopia. Being from the rural residence, home delivery, not taking antiretroviral prophylaxis, the absence of PMTCT intervention, and mixed infant feeding practices increased the risk of HIV transmission. Trial registration It is registered in the Prospero database: (PROSPERO 2017: CRD42017078232).

Teris Cheung, Joseph T. F. Lau, Johnson Z. Wang, P. K. H. Mo, Y. S. Ho

by Teris Cheung, Joseph T. F. Lau, Johnson Z. Wang, P. K. H. Mo, Y. S. Ho Objectives The highly infectious human papillomavirus (HPV) causes both genital warts and cervical cancer in women. In 2009, the prevalence of genital warts in Hong Kong was 203.7 per 100,000 person-years. Cervical cancer, more seriously, was the eight most common cancer among women and girls in Hong Kong, accounting for 2.3% of all new cancer cases in females in 2014. Cervical cancer is a significant global public health problem and HPV is a major risk factor leading to the development of cervical cancer. HPV is also the most common sexually transmitted disease among university students. This is the first study to examine the acceptability of HPV vaccines and associations with perceptions related to HPV and HPV vaccines among the male baccalaureate student population locally. Methods A self-administrative cross-sectional survey was used to assess whether male baccalaureate students from eight local Hong Kong universities intended to be immunized for HPV. The study also asked questions concerning how its subjects perceived HPV and HPV vaccines using the Health Belief Model. Data collection spanned from June to September 2015. A multiple stepwise regression model was used to examine associations between cognitive factors and subjects’ intention to take up the HPV vaccine. Results A total of 1,004 (83.7%) students aged 18 and 26 participated in this study. 23.3% found vaccinating for HPV acceptable, a level correlating with a number of indicators. Subjects were more likely to find vaccinating acceptable if 1) they knew something about HPV vaccines; 2) they understood that men were susceptible to infection by HPV; 3) they realised they could benefit by HPV vaccination, and 4) they were aware of the arguments for and against HPV vaccination, as disseminated by either the media or peers. Conclusions HPV remains a significant public health concern in Hong Kong and China more broadly. This study’s findings show a disconnect between the perceived and actual risk of being infected with the HPV vaccine among male baccalaureate students. This disconnect may be bridged by informing young men of the benefits of their being vaccinated against HPV, by removing the psychological and financial barriers that prevent them from taking up the vaccine and by improving how primary healthcare providers motivate them to get immunized.

Ayman Chit, Hossein Zivaripiran, Thomas Shin, Jason K. H. Lee, Antigona Tomovici, Denis Macina, David R. Johnson, Michael D. Decker, Jianhong Wu

by Ayman Chit, Hossein Zivaripiran, Thomas Shin, Jason K. H. Lee, Antigona Tomovici, Denis Macina, David R. Johnson, Michael D. Decker, Jianhong Wu Background Acellular pertussis vaccine studies postulate that waning protection, particularly after the adolescent booster, is a major contributor to the increasing US pertussis incidence. However, these studies reported relative (ie, vs a population given prior doses of pertussis vaccine), not absolute (ie, vs a pertussis vaccine naïve population) efficacy following the adolescent booster. We aim to estimate the absolute protection offered by acellular pertussis vaccines. Methods We conducted a systematic review of acellular pertussis vaccine effectiveness (VE) publications. Studies had to comply with the US schedule, evaluate clinical outcomes, and report VE over discrete time points. VE after the 5-dose childhood series and after the adolescent sixth-dose booster were extracted separately and pooled. All relative VE estimates were transformed to absolute estimates. VE waning was estimated using meta-regression modeling. Findings Three studies reported VE after the childhood series and four after the adolescent booster. All booster studies reported relative VE (vs acellular pertussis vaccine-primed population). We estimate initial childhood series absolute VE is 91% (95% CI: 87% to 95%) and declines at 9.6% annually. Initial relative VE after adolescent boosting is 70% (95% CI: 54% to 86%) and declines at 45.3% annually. Initial absolute VE after adolescent boosting is 85% (95% CI: 84% to 86%) and declines at 11.7% (95% CI: 11.1% to 12.3%) annually. Interpretation Acellular pertussis vaccine efficacy is initially high and wanes over time. Observational VE studies of boosting failed to recognize that they were measuring relative, not absolute, VE and the absolute VE in the boosted population is better than appreciated.

Abstract Background Malaria, despite being preventable and treatable, continues to be a major public health problem worldwide. The archipelago nation of Cape Verde is in a malaria pre-elimination phase with the highest potential to achieve the target goal of elimination in 2020. Methods Nationwide malaria epidemiological data were obtained from the Cape Verde health information system that includes the individual malaria case notification system from all of the country’s health structures. Each case is reported to the surveillance service then to the National Malaria Control Programme, which allowed for compilation in the national malaria case database. The database was analysed to assess the origin of the malaria cases, and incidence was calculated from 2010 to 2016 by sex and age. The health centre, health district and month of diagnosis were evaluated, as well as the sex and the age of the patients, allowing a direct descriptive analysis of national data to provide an up-to-date malaria epidemiological profile of the country. Malaria cases were classified as imported or indigenous, and then, geographical analyses were performed using a unique Geographical National Code with Quantum Geographic Information System 2.16.2 software to map the cases by municipalities. The overall temporal evolution of cases was analysed to assess their monthly and yearly variations from 2010 to 2016. Results Malaria is unstable in Cape Verde, with inter-annual variation and the majority of infections occurring in adult males (> 20 years). The indigenous cases are restricted to Santiago (96%) and Boavista (4%), while imported cases were recorded in all the nine inhabited islands, originating from neighbouring countries with ongoing malaria transmission; from Lusophone countries (25% from Angola, 25% from Guinea-Bissau), followed by the Republic of Senegal (12%) and Equatorial Guinea (10%). In 2010–2012, more imported (93 cases) than indigenous cases (26 cases) were observed; conversely, in 2013 and 2014, more indigenous cases (49) than imported cases (42) were reported. In 2015 there were 20 imported cases and only 7 indigenous cases. Finally, in 2016, there were 47 indigenous cases and 28 imported cases. The mapping of cases by municipality and country of origin was possible with GIS analyses. Conclusion While Cape Verde remains on track to achieve malaria elimination by 2020 owing to the reduction of the annual incidence to below 0.1%, the country still records cases of indigenous and imported malaria. However, the indigenous cases are exclusively confined to the Santiago and Boavista islands, while the imported cases recorded nationwide originate only from the African continent, mainly from adult men from the Lusophone countries. Cape Verde needs to target interventions to remove residual foci on Santiago and Boavista islands to reduce malaria lethality to zero and prevent its reintroduction from African countries via transmission across the archipelago. Cape Verde is a good example of local authority’s commitment to tackle malaria and work towards its elimination by strengthening the health and surveillance systems.

Vickers, A., Mushtaq, S., Woodford, N., Doumith, M., Livermore, D. M.

Pyrrolocytosines RX-04A-D are designed to bind to the bacterial 50S ribosomal subunit differently from currently-used antibiotics. The four analogs had broad anti-Gram-negative activity: RX-04A inhibited 94.7% of clinical Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa at 0.5-4 μg/ml, with no MICs >8 μg/ml. MICs for multi-resistant carbapenemase producers were up to two-fold higher than for control strains, with values ≥8 μg/ml for one Serratia isolate with porin and efflux lesions. mcr-1 did not affect MICs.

Roch, M., Varela, M. C., Taglialegna, A., Rose, W. E., Rosato, A. E.

Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a worse clinical outcome with increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus has a dual mode of action causing inhibition of the peptidoglycan synthesis and membrane depolarization. CF-associated MRSA infections remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for complicated skin infections and hospital-acquired pneumonia, the activity against CF- associated S. aureus infections has not been investigated. In this work, we studied the activity of telavancin against CF S. aureus strains collected from diverse geographical CF centers in the USA. We found that telavancin-MIC90 was 0.06 μg/ml, 8-fold lower than ceftaroline or daptomycin and 25-fold lower than linezolid and vancomycin. We demonstrate that telavancin at serum-free concentrations has rapid bactericidal activity with a decrease of more than 3 log10 CFU/ml during the first 4 to 6 hours of treatment, performing better in this assay than vancomycin and ceftaroline, including S. aureus resistant to ceftaroline.Telavancin resistance was infrequent (0.3%), although we found that it can occur in- vitro in both CF- and non-CF S. aureus strains by progressive passages with sub-inhibitory concentrations. Genetic analysis of telavancin in-vitro mutants showed gene polymorphisms in cell wall and virulence genes, and increased survival in a Galleria mellonella infection model. Thus, we conclude that telavancin represents a promising therapeutic option for CF infections with potent in-vitro activity and low resistance potential.

Gaubert, Mélanie; Marlinge, Marion; Kerbaul, François; Resseguier, Noemie; Laine, Marc; Cautella, Jennifer; Cordier, Charlotte; Colomb, Benjamin; Kipson, Nathalie; Thuny, Franck; Mottola, Giovanna; Fenouillet, Emmanuel; Ruf, Jean; Paganelli, Franck; Guieu, Régis; Bonello, Laurent

Objectives: To investigate whether adenosine A2A receptors lead to vasodilation and positive inotropic function under stimulation and whether they play a role in the control of blood pressure in patients with cardiogenic shock. Design: Prospective observational study. Setting: Monocentric, Hopital Nord, Marseille, France. Subjects: Patients with cardiogenic shock (n = 16), acute heart failure (n = 16), and acute myocardial infarction (n = 16). Interventions: None. Measurements and Main Results: Arterial adenosine plasma level and A2A receptor expression on peripheral blood mononuclear cells were evaluated by mass spectrometry and Western blot, respectively, at admission and after 24 hours. Hemodynamic parameters, including systemic vascular resistance, were also assessed. Mean adenosine plasma level at admission was significantly higher in patients with cardiogenic shock (2.74 ± 1.03 µM) versus acute heart failure (1.33 ± 0.27) or acute myocardial infarction (1.19 ± 0.27) (normal range, 0.4–0.8 µM) (p < 0.0001). No significant correlation was found between adenosine plasma level and systemic vascular resistance. Mean adenosine plasma level decreased significantly by 24 hours after admission in patients with cardiogenic shock (2.74 ± 1.03 to 1.53 ± 0.68; p < 0.001). Mean A2A receptor expression was significantly lower in patients with cardiogenic shock (1.18 ± 0.11) versus acute heart failure (1.18 ± 0.11 vs 1.39 ± 0.08) (p = 0.005). Conclusions: We observed high adenosine plasma level and low A2A receptor expression at admission in patients with cardiogenic shock versus acute heart failure or acute myocardial infarction. This may contribute to the physiopathology of cardiogenic shock. Drs. Guieu and Bonello contributed equally to this work. Drs. Fenouillet and Ruf disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: guieu.regis@orange.fr Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

John R. Su, Carmen Ng, Paige W. Lewis, Maria V. Cano

by John R. Su, Carmen Ng, Paige W. Lewis, Maria V. Cano Human immunodeficiency virus (HIV) causes immune dysregulation, potentially affecting response to vaccines in infected persons. We investigated if unexpected adverse events (AEs) or unusual patterns of AEs after vaccination were reported among HIV-positive persons. We searched for domestic reports among HIV-positive persons to the Vaccine Adverse Event Reporting System (VAERS) during 1990–2016. We analyzed reports by age group (…

Sami Ullah, Hanita Daud, Sarat C. Dass, Hadi Fanaee-T, Alamgir Khalil

by Sami Ullah, Hanita Daud, Sarat C. Dass, Hadi Fanaee-T, Alamgir Khalil Identifying the abnormally high-risk regions in a spatiotemporal space that contains an unexpected disease count is helpful to conduct surveillance and implement control strategies. The EigenSpot algorithm has been recently proposed for detecting space-time disease clusters of arbitrary shapes with no restriction on the distribution and quality of the data, and has shown some promising advantages over the state-of-the-art methods. However, the main problem with the EigenSpot method is that it cannot be adapted to detect more than one spatiotemporal hotspot. This is an important limitation, since, in reality, we may have multiple hotspots, sometimes at the same level of importance. We propose an extension of the EigenSpot algorithm, called Multi-EigenSpot that is able to handle multiple hotspots by iteratively removing previously detected hotspots and re-running the algorithm until no more hotspots are found. In addition, a visualization tool (heatmap) has been linked to the proposed algorithm to visualize multiple clusters with different colors. We evaluated the proposed method using the monthly data on measles cases in Khyber-Pakhtunkhwa, Pakistan (Jan 2016- Dec 2016), and the efficiency was compared with the state-of-the-art methods: EigenSpot and Space-time scan statistic (SaTScan). The results showed the effectiveness of the proposed method for detecting multiple clusters in a spatiotemporal space.

Wendt L, Kämper L, Schmidt M, et al.

AbstractThe Ebola virus (EBOV) matrix protein VP40 drives budding of virions and encodes 2 overlapping late domain motifs at amino acid positions 7–13 (PTAPPEY). However, these motifs are not absolutely essential for replication in cell culture, and recently a potential third late domain motif (YPx(6)I) was proposed at amino acid positions 18–26 of VP40. To analyze the importance of this motif in viral budding, we used a transcription and replication-competent virus-like particle system. Using this system, we show that this motif does not contribute to EBOV budding or particle propagation.

Almarzoky Abuhussain, S. S., Kuti, J. L., Nicolau, D. P.

The role of inhalational combination therapy when treating carbapenem resistant Pseudomonas aeruginosa and Klebsiella pneumoniae with newer beta-lactam/beta-lactamase inhibitors has not been established. Using a 72 hour in vitro pharmacodynamic chemostat model, we simulated the human exposures achieved in epithelial lining fluid (ELF) following intravenous ceftazidime-avibactam (CZA) 2.5g q8h alone and in combination with inhaled amikacin (AMK) 400mg q12h, a reformulated aminoglycoside designed for inhalational administration, against 3 P. aeruginosa (CZA MICs: 4/4-8/4 μg/ml; AMK-I MICs: 8-64 μg/ml) and 3 K. pneumoniae (CZA: 1/4-8/4 μg/ml; AMK-I: 32-64 μg/ml). Combination therapy resulted in a significant reduction in 72 hour colony forming units (CFU) compared with CZA monotherapy against 2 of 3 P. aeruginosa (-4.14 log10CFU/ml, P= 0.027; -1.42 log10CFU/ml, P=0.020; and -0.4 log10CFU/ml, P= 0.298) and 2 of 3 K. pneumoniae (0.04 log10CFU/ml, P=0.963; -4.34 log10CFU/ml, P < 0.001; and -2.34 log10 CFU/ml, P=0.021). When measured by the area under the bacterial growth curve (AUBC) over 72 hours, significant reductions were observed in favor of the combination regimen against all 6 isolates tested. AMK-I combination therapy successfully suppressed CZA resistance development in one K. pneumoniae harboring blakpc3 that was observed during CZA monotherapy. These studies suggest a beneficial role for combination therapy with intravenous CZA and inhaled AMK when treating pneumonia caused by carbapenem resistant Gram-negative bacteria.

David Lebeaux, Emmanuelle Bergeron, Jérémy Berthet, Juliette Djadi-Prat, Delphine Mouniée, Patrick Boiron, Olivier Lortholary, Véronica Rodriguez-Nava

Nocardia, a Gram-positive bacterium, is responsible for rare and severe infections. Accurate microbiological data are essential to guide antibiotic treatment. Our primary objective was to describe species identification and results of antimicrobial susceptibility testing (AST) for Nocardia isolates analysed over a 6-year period. Secondary objectives were to study temporal trends in species distribution and AST results.

Alfredo Ponce-de-Leon, Eduardo Rodríguez-Noriega, Rayo Morfín-Otero, Dora P. Cornejo-Juárez, Juan C. Tinoco, Areli Martínez-Gamboa, Carmen J. Gaona-Tapia, M. Lourdes Guerrero-Almeida, Alexandra Martin-Onraët, José Luis Vallejo Cervantes, José Sifuentes-Osornio

by Alfredo Ponce-de-Leon, Eduardo Rodríguez-Noriega, Rayo Morfín-Otero, Dora P. Cornejo-Juárez, Juan C. Tinoco, Areli Martínez-Gamboa, Carmen J. Gaona-Tapia, M. Lourdes Guerrero-Almeida, Alexandra Martin-Onraët, José Luis Vallejo Cervantes, José Sifuentes-Osornio Antimicrobial resistance is an increasing worldwide concern, which poses unique challenges for the effective prevention and treatment of several infections, especially the ones triggered by organisms producing extended-spectrum β-lactamases (ESBL). Here, we present the surveillance results of the Study for Monitoring Antimicrobial Resistance Trends (SMART) of Gram-negative bacilli isolated from intra-abdominal infections (IAI, n = 1,235) and urinary-tract infections (UTI, n = 2,682), collected in Mexico from 2009 to 2015. Susceptibility and ESBL status were determined according to the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method. Both E. coli (57%) and K. pneumoniae (12%) were the most frequently reported organisms, as well as the ones with the highest prevalence of ESBL-producing isolates (54% and 39%, respectively). The overall prevalence of ESBL-producing organisms was higher in nosocomial infections than in community-acquired infections (21% vs. 27%). The ESBL rates were 36% for IAI (953/2,682) and 37% for UTI (461/1,235). In addition, ertapenem, imipenem and amikacin were the antibiotics that mostly preserved bacterial susceptibility. Our results show consistency with global trends, although higher than the rates observed in Latin America.

Abstract Background Malaria is one of the major public health problems in Myanmar. Village health volunteers (VHV) are the key malaria diagnosis and treatment service provider at community level in addition to basic health staffs (BHS). This countrywide analysis aimed to assess and compare the accessibility to- and quality of malaria care (treatment initiation, treatment within 24 h and complete treatment delivery) between VHV and BHS in Myanmar. Methods This was a retrospective cohort study using record review of routinely collected programme data available in electronic format. All patients with undifferentiated fever screened and diagnosed for malaria in January–December 2015 by VHV and BHS under National Malaria Control Programme in Myanmar were included in the study. Unadjusted and adjusted prevalence ratios (aPR) were calculated to assess the effect of VHV/BHS on receipt of treatment by patients. Results Of 978,735 undifferentiated fever patients screened in 2015, 11.0% of patients were found malaria positive and the malaria positivity in VHV and BHS group were 11.1 and 10.9% respectively. Access to malaria care: higher proportion of children aged 5–14 years (21.8% vs 17.3%) and females (43.7% vs 41.8%) with fever were screened for malaria by VHV compared to BHS. However, the same for children aged

Alvarez, R. A., Zavala-Araiza, D., Lyon, D. R., Allen, D. T., Barkley, Z. R., Brandt, A. R., Davis, K. J., Herndon, S. C., Jacob, D. J., Karion, A., Kort, E. A., Lamb, B. K., Lauvaux, T., Maasakkers, J. D., Marchese, A. J., Omara, M., Pacala, S. W., Peischl, J., Robinson, A. L., Shepson, P. B., Sweeney, C., Townsend-Small, A., Wofsy, S. C., Hamburg, S. P.

Methane emissions from the U.S. oil and natural gas supply chain were estimated using ground-based, facility-scale measurements and validated with aircraft observations in areas accounting for ~30% of U.S. gas production. When scaled up nationally, our facility-based estimate of 2015 supply chain emissions is 13 ± 2 Tg/y, equivalent to 2.3% of gross U.S. gas production. This value is ~60% higher than the U.S. EPA inventory estimate, likely because existing inventory methods miss emissions released during abnormal operating conditions. Methane emissions of this magnitude, per unit of natural gas consumed, produce radiative forcing over a 20-year time horizon comparable to the CO2 from natural gas combustion. Significant emission reductions are feasible through rapid detection of the root causes of high emissions and deployment of less failure-prone systems.

Stainton, S. M., Abdelraouf, K., Utley, L., Pucci, M. J., Lister, T., Nicolau, D. P.

SPR741 is a novel agent with structural similarity to polymyxins, capable of potentiating the activity of various classes of antibiotics. Previously published studies indicated that although Enterobacteriacae isolates had minimal susceptibilities to azithromycin (AZM), the in vitro antimicrobial activity of AZM against Enterobacteriacae was enhanced when combined with SPR741. The current study evaluated the in vivo activity of human-simulated regimens (HSR) of AZM equivalent to clinical doses of 500 mg IV q24h and SPR741 400 mg q8h IV (1h infusion) alone and in combination against multi-drug resistant (MDR) Enterobacteriacae. We studied 30 MDR Enterobacteriacae isolates expressing a wide spectrum of β-lactamases (ESBL, NDM, VIM and KPC) inclusive of a subset of isolates positive for genes conferring macrolide resistance (mphA, mphE, ermB and msr). In vivo activity was assessed as the change in log10CFU/thigh at 24 h compared with 0 h. Treatment with AZM alone was associated with net growth of 2.60 ± 0.83 log10CFU/thigh. Among isolates with AZM MIC ≤ 16 mg/L, treatment with AZM/SPR741was associated with an average reduction in bacterial burden of -0.53 ± 0.82 log10CFU/thigh and stasis to 1-log kill was observed in 9/11 isolates (81.8%). Combination therapy of AZM/SPR741 HSR showed promising in vivo activity against MDR Enterobacteriacae for isolates with AZM MIC ≤ 16 mg/L, including those producing a variety of β-lactamases. These data support a potential role for AZM/SPR741 for treatment of infections due to MDR Enterobacteriacae.

Abstract Background Long-lasting insecticidal nets (LLINs) are a key tool for malaria prevention and control. Currently, the recommended serviceable life of an LLIN is 3 years under field conditions. However, field studies show considerable variation in LLIN lifespan, from less than 2 years to more than 4 years. This study aimed to determine the attrition, physical integrity, functional survival, and bio-efficacy of LLINs under field conditions in south-central Ethiopia. Methods In October 2014, 7740 LLINs (PermaNet® 2.0) were distributed to 3006 households. Among the distributed LLINs, a cohort study involving 1532 LLINs in 659 households was carried out from October 2014 to November 2016. Data were collected every 6 months by observation, and through interviews with the heads of households. The proportional hole index was used to categorize LLINs as either serviceable or torn. In addition, 120 randomly selected LLINs were tested for bio-efficacy. Results The overall attrition of LLINs was 96% (n = 993) during the study period. The nets’ attrition was mainly due to disposal (64.2%; n = 638). The proportion of LLINs with a hole size 0.5 cm or larger was 79.5% after 24 months. The use of the net on the previous night and having a clean net were associated with a good physical integrity. However, living in a household more than 1 km away from the mosquitoes’ breeding site was associated with poor physical integrity. By the 24th month, only 4% of the nets met the criteria for functional survival. The median functional survival time of the nets was 12 months. A longer functional survival was associated with having a clean net, and shorter survival was associated with living in a household more than 1 km away from the mosquitoes’ breeding site. The PermaNet® 2.0 met the criteria of effective bio-efficacy up to month 24 after distribution. Conclusions The study showed that the median serviceable life of LLINs is only 12 months. However, the bio-efficacy of the LLINs is acceptable for at least 24 months. Therefore, stronger and more efficient LLINs need to be developed for conditions similar to those studied here.

Liu F, Tzeng W, Horner L, et al.

AbstractBackgroundAlthough ferret antisera used in influenza surveillance did not detect antigenic drift of A(H1N1)pdm09 viruses during 2015-16 season, low vaccine effectiveness was reported in adults. We investigated the immune basis of low responses to circulating A(H1N1)pdm09 viruses following vaccination.MethodsOver 300 paired adult (18-49 yrs) pre and post-vaccination sera collected in 6 seasons (2010-11 to 2015-16) were analyzed by hemagglutination inhibition assays to evaluate the antibody responses to thirteen A(H1N1) viruses circulated from 1977 to 2016. Microneutralization and serum adsorption assays were used to verify 163K- and 223R-specificity of antibodies.ResultsIndividual antibody profiles to A(H1N1) viruses revealed three priming patterns: USSR/77-, TW/86- or NC/99-priming. Over 20% of adults had reduced titers to cell-propagated circulating 6B.1 and 6B.2 A(H1N1)pdm09 viruses compared to the A/California/07/2009 vaccine virus X-179A. Significantly reduced antibody reactivity to circulating viruses bearing K163Q was only observed in USSR/77-primed cohort, whereas significantly lower reactivity caused by egg-adapted Q223R change was detected across all 3 cohorts.ConclusionBoth 163K-specificity driven by immune priming and 223R-specificity from egg-adapted changes in the vaccine contributed to low responses to circulating A(H1N1)pdm09 viruses following vaccination. Our study highlights the need to incorporate human serology in influenza surveillance and vaccine strain selection.

Abstract Background Utilization of long-lasting insecticidal nets (LLIN) has been associated with reduction of malaria incidence, especially among children. The 2013 Nigeria Demographic and Health Survey revealed Osun State had the least proportion (5.7%) of under-five children (U5) who slept under LLIN the night before the survey. A study was conducted to assess caregivers’ knowledge about LLIN, utilization of LLIN and factors influencing LLIN use among U5 in Osun State, Nigeria. Methods A cross-sectional study was carried out among 1020 mothers/caregivers of U5 selected from six communities in Osun State using a multistage sampling technique. A pre-tested interviewer administered questionnaire was used to collect information on socio-demographic characteristics, mothers’ knowledge about LLIN, ownership and utilization of LLIN and factors influencing use of LLIN in U5. Questions on knowledge about LLIN were scored and categorized into good (scored ≥ 5) and poor (score 

Umeyama, T., Hayashi, Y., Shimosaka, H., Inukai, T., Yamagoe, S., Takatsuka, S., Hoshino, Y., Nagi, M., Nakamura, S., Kamei, K., Ogawa, K., Miyazaki, Y.

A pan-azole-resistant Aspergillus fumigatus strain with the cyp51A mutations Gly138Ser and Asn248Lys was isolated from a patient receiving long-term voriconazole treatment. PCR fragments containing cyp51A with the mutations were introduced along with Cas9 protein and single-guide RNA into the azole-resistant/susceptible strains. Recombinant strains showed increased susceptibility via the replacement of Ser138 by glycine. Genetic recombination, which has been hampered thus far in clinical isolates, can now be achieved using Cas9/CRISPR genome editing.

Alba Cortés, Rafael Toledo, Cinzia Cantacessi

Whilst a wealth of data indicate that infections by gastrointestinal helminths are accompanied by significant alterations in the composition of the vertebrate gut flora, little is known of the immune-molecular mechanisms that regulate host–parasite–microbiota interactions. ‘Traditional’ experimental models of gastrointestinal helminthiases, in which the role(s) of each of the components of this triad can be tested, provide an opportunity to advance research in this area. In this article, we propose the Echinostoma caproni–mouse system as a potentially useful tool for studies of the role of the host gut microbiota in preventing pathology and inducing parasite clearance via interleukin (IL)-25, an epithelial-derived alarmin with key roles in antihelminth immunity and maintenance of gut homeostasis.

Inka Liesmaa, Riitta Paakkanen, Asko Järvinen, Ville Valtonen, Marja-Liisa Lokki

by Inka Liesmaa, Riitta Paakkanen, Asko Järvinen, Ville Valtonen, Marja-Liisa Lokki Introduction Homozygous deficiencies of complement C4A or C4B are detected in 1–10% of populations. In genome-wide association studies C4 deficiencies are missed because the genetic variation of C4 is complex. There are no studies where the clinical presentation of these patients is analyzed. This study was aimed to characterize the clinical features of patients with homozygous C4A or C4B deficiency. Material and methods Thirty-two patients with no functional C4A, 87 patients with no C4B and 120 with normal amount of C4 genes were included. C4A and C4B numbers were assessed with genomic quantitative real-time PCR. Medical history was studied retrospectively from patients’ files. Results Novel associations between homozygous C4A deficiency and lymphoma, coeliac disease and sarcoidosis were detected. These conditions were present in 12.5%, (4/32 in patients vs. 0.8%, 1/120, in controls, OR = 17.00, 95%CI = 1.83–158.04, p = 0.007), 12.5% (4/32 in patients vs. 0%, 0/120 in controls, OR = 1.14, 95%CI = 1.00–1.30, p = 0.002) and 12.5%, respectively (4/32 in patients vs. 2.5%, 3/120 in controls, OR = 5.571, 95%CI = 1.79–2.32, p = 0.036). In addition, C4A and C4B deficiencies were both associated with adverse drug reactions leading to drug discontinuation (34.4%, 11/32 in C4A-deficient patients vs. 14.2%, 17/120 in controls, OR = 3.174, 95%CI = 1.30–7.74, p = 0.009 and 28.7%, 25/87 in C4B-deficient patients, OR = 2.44, 95%CI = 1.22–4.88, p = 0.010). Conclusion This reported cohort of homozygous deficiencies of C4A or C4B suggests that C4 deficiencies may have various unrecorded disease associations. C4 gene should be considered as a candidate gene in studying these selected disease associations.

Charretier, Y., Diene, S. M., Baud, D., Chatellier, S., Santiago-Allexant, E., van Belkum, A., Guigon, G., Schrenzel, J.

Multidrug-resistant Acinetobacter baumannii infection has recently emerged as a worldwide clinical problem and colistin is increasingly being used for last resort therapy. Despite its favorable bacterial killing, resistance and heteroresistance (HR) to colistin have been described. The purpose of the present study is to investigate the role of the PmrAB regulatory pathway in laboratory-selected mutants representative of global epidemic strains. From three unrelated A. baumannii clinical strains (Sequence Type 2, 3 and 20), eight colistin resistant mutants were selected. Half of the mutants showed HR to colistin according to the reference method (Population Analysis Profiling), whereas the other half exhibited stable resistance. M12I mutation within pmrA and M308R, S144KLAGS and P170L mutations for pmrB, were associated with HR to colistin while T235I, A226T and P233S mutations within pmrB were associated with stable resistance. The transcripts levels of the pmrCAB operon were upregulated in all the mutants. Compensatory mutations were explored for some mutants. A single mutant (T235I) displayed a compensatory mutation through ISAba1 mobilization within the pmrB gene that was associated with the loss of colistin resistance. The mutant resistance phenotype associated with T235I was partially restored in a trans-complementation assay turning to HR. The level of colistin resistance is correlated with the level of expression of pmrC in the trans-complemented strains. This report shows the role of different mutations in the PmrAB regulatory pathway and warns on the development of colistin HR that could be present but not easily detected through routine testing.

Abstract Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy worldwide. Primaquine is the only licensed drug that effectively removes Plasmodium vivax hypnozoites from the human host and prevents relapse. While well tolerated by most recipients, primaquine can cause haemolysis in G6PD deficient individuals and is, therefore, underused. Rapid diagnostic tests (RDTs) could permit ascertainment of G6PD status outside of laboratory settings and hence safe treatment in remote areas. The performance of the fluorescent spot test (Trinity, Ireland; FST) and a G6PD RDT (Carestart, USA) against spectrophotometry were assessed. Methods Participants were enrolled during cross-sectional surveys in Laos and by purposive sampling in Cambodia. FST and RDT were performed during village surveys and 3 mL of venous blood was collected for subsequent G6PD measurement by spectrophotometry. Results A total of 757 participants were enrolled in Laos and 505 in Cambodia. FST and RDT performed best at 30% cut-off activity and performed significantly better in Laos than in Cambodia. When defining intermediate results as G6PD deficient, the FST had a sensitivity of 100% (95%CI 90–100) and specificity of 90% (95%CI 87.7–92.2) in Laos and sensitivity of 98% (94.1–99.6) and specificity of 71% (95%CI 66–76) in Cambodia (p 

Sato, T., Shiraishi, T., Hiyama, Y., Honda, H., Shinagawa, M., Usui, M., Kuronuma, K., Masumori, N., Takahashi, S., Tamura, Y., Yokota, S.-i.

Colistin is a last-line drug for multidrug-resistant Gram-negative bacteria. We previously reported four plasmid-mediated colistin resistance (mcr) gene-negative colistin-resistant Escherichia coli clinical isolates, including the major pathogenic and fluoroquinolone-resistant strains O25b:H4-ST131-H30Rx [isolates SRE34 and SRE44, minimum inhibitory concentration (MIC) for colistin = 16 mg/L] and non-x (SME296, MIC = 8 mg/L), and O18-ST416 (SME222, MIC = 4 mg/L). Herein, we investigated the colistin resistance mechanism, and identified novel amino acid substitutions or deletion in the PmrAB two-component system that activates eptA (encoding a phosphoethanolamine transferase) and arnT (encoding an undecaprenyl phosphate-alpha-4-amino-4-deoxy-l-arabinose arabinosyl transferase) in all colistin-resistant isolates. SRE34 possessed deletion 27-45_LISVFWLWHESTEQIQLFE in PmrB, SRE44 possessed substitution L105P in PmrA, and both SME222 and SME296 included substitution G206D in PmrB. Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry revealed that lipid A is modified with phosphoethanolamine in all four isolates. Deletion of pmrAB decreased colistin MICs to 0.5 mg/L and lowered eptA/arnT expression. Chromosomal replacement of mutated pmrA/pmrB into colistin-susceptible O25b:H4-ST131 strain SME98 (colistin MIC = 0.5 mg/L) increased the colistin MIC to that of the respective parent colistin-resistant isolate. In addition, mutated-pmrAB-replaced SME98 mutants showed no significant differences in bacterial growth and competition culture with the parent strain, except for the mutant with L105P in PmrA, whose growth was significantly suppressed in the presence of the parent strain. In conclusion, some O25b:H4-ST131 strains appear to confer colistin resistance via phosphoethanolamine modification of lipid A through amino acid changes in PmrAB, and the amino acid changes in PmrB does not influence bacterial growth.

Neyens, Ron R.; Gaskill, George E.; Chalela, Julio A.

Objectives: Anti-N-methyl-D-asparate receptor encephalitis is considered an immune-mediated form of encephalitis with paraneoplastic and nonparaneoplastic forms. Delay in recognition is common and patients typically present to the ICU without a diagnosis or with complications following a delayed diagnosis. The aim of this review is to provide a focused overview for the ICU clinician regarding presentation, diagnosis, and critical care management. Data Sources, Study Selection, and Data Extraction: PubMed database search with manual review of articles involving anti-N-methyl-D-asparate receptor encephalitis. Data Synthesis: Anti-N-methyl-D-asparate receptor encephalitis is increasingly encountered in the ICU. The cascade of events initiating anti-N-methyl-D-asparate receptor antibody formation may involve an infectious trigger particularly in the setting of teratoma. Following a prodrome, most patients develop psychiatric symptoms followed by movement disorder. Classical, psychiatric, and catatonic phenotypes may be distinguished based on the presence and severity of symptoms. Early immunotherapy and low initial cerebrospinal fluid inflammation are independent predictors of positive outcomes in ICU patients. Concomitant organ failure, status epilepticus, and the identification of a tumor did not influence outcome in critically ill patients. Supportive care in the ICU includes management of various manifestations of dyskinesia, status epilepticus, autonomic disorders, and the need for general sedation. Common treatment strategies and limitations are discussed including the emerging role of bortezomib. Conclusions: Intensivists should be familiar with the presentation and management of anti-N-methyl-D-asparate receptor encephalitis. Early diagnosis and immediate implementation of steroids, immunoglobulins, and/or plasmapheresis and immune therapy are associated with a good neurologic outcome although response may be delayed. The selection and timing of second-line immune therapy requires further study. Dr. Neyens disclosed off-label product use of IV immune globulin, rituximab, and bortezomib. Dr. Gaskill disclosed off-label product use of rituximab and bortezomib. Dr. Chalela has disclosed that he does not have any potential conflicts of interest. For information regarding this article, E-mail: Chalela@musc.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Kim, I. H., Kim, S.-Y., Park, N.-Y., Wen, Y., Lee, K.-W., Yoon, S.-Y., Jie, H., Lee, K.-H., Kim, K.-S.

Vibrio vulnificus, an opportunistic human pathogen, produces cyclo (L-Phe-L-Pro) (cFP), which serves as a signaling molecule controlling the ToxR-dependent expression of innate bacterial genes, and also as a virulence factor eliciting pathogenic effects on human cells by enhancing intracellular reactive oxygen species levels. We found that cFP facilitated the protection of V. vulnificus against hydrogen peroxide. At a concentration of 1 mM, cFP enhanced the level of the transcriptional regulator RpoS which, in turn, induced expression of katG, encoding hydroperoxidase I, an enzyme that detoxifies H2O2 to overcome the oxidative stress. We found that cFP upregulated the transcription of the histone-like proteins vHUα and vHUβ through the cFP-dependent regulator LeuO. LeuO binds directly to upstream regions of vhuα and vhuβ to enhance transcription. vHUα and vHUβ then enhance the level of RpoS post-transcriptionally by stabilizing the mRNA. This cFP-mediated ToxR-LeuO-vHUαβ-RpoS pathway also upregulates genes known to be members of the RpoS regulon, suggesting that cFP acts as a cue for the signaling pathway responsible for both the RpoS and the LeuO regulons. Taken together, this study shows that cFP plays an important role as a virulence factor as well as a signal for the protection of the cognate pathogen.

Nair, S., Li, X., Arya, G. A., McDew-White, M., Ferrari, M., Nosten, F., Anderson, T. J. C.

Fitness costs are key determinants of whether drug resistance alleles establish and how fast they spread within populations. More than 125 different kelch13 alleles, each containing a different amino acid substitution, have arisen in SE Asian malaria parasite (Plasmodium falciparum) populations under artemisinin selection over the past 15 years in a dramatic example of a soft selective event. However, just one of these alleles (C580Y) is now outcompeting other alleles in multiple different countries and is spreading towards fixation. Here we examine the fitness consequences of C580Y, relative to another less successful kelch13 mutation (R561H), to try to explain the distinctive dynamics of C580Y. We hypothesized that C580Y will show lower fitness costs relative to other kelch13 substitutions in the absence of artemisinin treatment. We used CRISPR/Cas9 methods to introduce single mutations (C580Y or R561H), or synonymous control edits into a wildtype parasite isolated on the Thailand-Myanmar border, conducted replicated head-to-head competition assays, and determined the outcome of competition using deep sequencing of kelch13 amplicons. Contrary to our predictions, these experiments reveal that C580Y carries higher fitness costs (s=0.15 ± 0.008 [1 s.e.]) than R561H (s=0.084 ± 0.005). Furthermore, R561H outcompetes C580Y in direct competition (s=0.065 ± 0.004). We conclude that fitness costs of C580Y in isolation are unlikely to explain the rapid spread of this substitution.

Hailay Abrha Gesesew, Paul Ward, Kifle Woldemichael, Lillian Mwanri

by Hailay Abrha Gesesew, Paul Ward, Kifle Woldemichael, Lillian Mwanri Background Several studies reported that the majority of deaths in HIV-infected people are documented in their early antiretroviral therapy (ART) follow-ups. Early mortality refers to death of people on ART for follow up period of below 24 months due to any cause. The current study assessed predictors of early HIV mortality in Southwest Ethiopia. Methods We have conducted a retrospective analysis of 5299 patient records dating from June 2003- March 2015. To estimate survival time and compare the time to event among the different groups of patients, we used a Kaplan Meir curve and log-rank test. To identify mortality predictors, we used a cox regression analysis. We used SPSS-20 for all analyses. Results A total of 326 patients died in the 12 years follow-up period contributing to 6.2% cumulative incidence and 21.7 deaths per 1000 person-year observations incidence rate. Eighty-nine percent of the total deaths were documented in the first two years follow up—an early-term ART follow up. Early HIV mortality rates among adults were 50% less in separated, divorced or widowed patients compared with never married patients, 1.6 times higher in patients with baseline CD4 count…

Subissi L, Keita M, Mesfin S, et al.

AbstractThe 2014–2016 Ebola virus (EBOV) disease outbreak affected over 29000 people and left behind the biggest cohort (over 17000 individuals) of Ebola survivors in history. Although the persistence of EBOV in body fluids of survivors was reported before the recent outbreak, new evidence revealed that the virus can be detected up to 18 months in the semen, which represents the biggest risk of Ebola resurgence in affected communities. In this study, we review the knowledge on the Ebola flare-ups that occurred after the peak of the 2014–2016 Ebola epidemic in West Africa.

Rachel Groppo, Joshua DiNapoli, Kwang Il Jeong, Michael Kishko, Nicholas Jackson, Harold Kleanthous, Simon Delagrave, Linong Zhang, Mark Parrington

by Rachel Groppo, Joshua DiNapoli, Kwang Il Jeong, Michael Kishko, Nicholas Jackson, Harold Kleanthous, Simon Delagrave, Linong Zhang, Mark Parrington A safe and effective vaccine against RSV remains an important unmet public health need. Intranasally (IN) delivered live-attenuated vaccines represent the most extensively studied approach for immunization of RSV-naïve infants and children, however, achieving an effective balance of attenuation and immunogenicity has proven challenging. Here we report pre-clinical immunogenicity and efficacy data utilizing a live-attenuated vaccine candidate, RGΔM2-2, which was obtained by deleting the M2-2 open reading frame from the genome of the MSA1 clinical isolate. Intramuscular (IM) administration of RGΔM2-2 in cotton rats induced immunity and protective efficacy that was comparable to that induced by intranasal (IN) immunization. In contrast, the protective efficacy of RGΔM2-2 delivered by the IM route to African green monkeys was substantially reduced as compared to the efficacy following IN administration, despite comparable levels of serum neutralizing antibodies. This result suggests that mucosal immunity may play an important role in RSV protection. The RGΔM2-2 vaccine also demonstrated different attenuation profiles when tested in cotton rats, non-human primates, and a human airway epithelial (HAE) cell model. The data suggest RGΔM2-2 is less attenuated than a similarly designed vaccine candidate constructed on the A2 genetic background. These findings have important implications with regard to both the design and the preclinical safety testing of live-attenuated vaccines.