Michael Doherty, Wendy Jenkins, Helen Richardson, Aliya Sarmanova, Abhishek Abhishek, Deborah Ashton, Christine Barclay, Sally Doherty, Lelia Duley, Rachael Hatton, Frances Rees, Matthew Stevenson, Weiya Zhang

Nurse-led gout care is efficacious and cost-effective compared with usual care. Our findings illustrate the benefits of educating and engaging patients in gout management and reaffirm the importance of a treat-to-target urate-lowering treatment strategy to improve patient-centred outcomes.

Ndivhuho A Makhado, Edith Matabane, Mauro Faccin, Claire Pinçon, Agathe Jouet, Fairouz Boutachkourt, Léonie Goeminne, Cyril Gaudin, Gugu Maphalala, Patrick Beckert, Stefan Niemann, Jean-Charles Delvenne, Michel Delmée, Lufuno Razwiedani, Maphoshane Nchabeleng, Philip Supply, Bouke C de Jong, Emmanuel André

A substantial number of MDR tuberculosis cases harbouring the Ile491Phe mutation in the rpoB gene in South Africa are missed by current diagnostic strategies, resulting in ineffective first-line treatment, continued amplification of drug resistance, and concurrent silent spread in the community.

Catherine H Bozio, Jeni Vuong, E Kainne Dokubo, Mosoka P Fallah, Lucy A McNamara, Caelin C Potts, John Doedeh, Miatta Gbanya, Adam C Retchless, Jaymin C Patel, Thomas A Clark, Henry Kohar, Thomas Nagbe, Peter Clement, Victoria Katawera, Nuha Mahmoud, Harouna M Djingarey, Anne Perrocheau, Dhamari Naidoo, Mardia Stone, Roseline N George, Desmond Williams, Alex Gasasira, Tolbert Nyenswah, Xin Wang, LeAnne M Fox, Liberian Meningococcal Disease Outbreak Response Team

This outbreak featured high attack and case fatality rates. Clinical presentation was broadly consistent with previous meningococcal disease outbreaks, but predominance of gastrointestinal symptoms was unusual compared with previous African meningitis epidemics. The outbreak strain was genetically similar to NmC CC10217, which caused meningococcal disease outbreaks in Niger and Nigeria. CC10217 had previously been identified only in the African meningitis belt.

Jane S Hocking, Meredith Temple-Smith, Rebecca Guy, Basil Donovan, Sabine Braat, Matthew Law, Jane Gunn, David Regan, Alaina Vaisey, Liliana Bulfone, John Kaldor, Christopher K Fairley, Nicola Low, ACCEPt Consortium

These findings, in conjunction with evidence about the feasibility of sustained uptake of opportunistic testing in primary care, indicate that sizeable reductions in chlamydia prevalence might not be achievable.

Linda S Chesterton, Milica Blagojevic-Bucknall, Claire Burton, Krysia S Dziedzic, Graham Davenport, Sue M Jowett, Helen L Myers, Raymond Oppong, Trishna Rathod-Mistry, Danielle A van der Windt, Elaine M Hay, Edward Roddy

A single corticosteroid injection shows superior clinical effectiveness at 6 weeks compared with night-resting splints, making it the treatment of choice for rapid symptom response in mild or moderate carpal tunnel syndrome presenting in primary care.

The Lancet

The National Institute for Health and Care Excellence (NICE) has published draft guidelines for the clinical management of pelvic organ prolapse and stress urinary incontinence. The guidelines, which are open for public consultation until Nov 19, recommend that women, first and foremost, be offered lifestyle interventions, physical and behavioural therapies, and medication before surgical options are considered. Women who do choose to have surgery must be fully informed of the risks and referred to a specialist.

Ngozi A Erondu, Jerry Martin, Robert Marten, Gorik Ooms, Robert Yates, David L Heymann

In the wake of the recent west African Ebola epidemic, there is global consensus on the need for strong health systems; however, agreement is less apparent on effective mechanisms for establishing and maintaining these systems, particularly in resource-constrained settings and in the presence of multiple and sustained stresses (eg, conflict, famine, climate change, and globalisation). The construction of the International Health Regulations (2005) guidelines and the WHO health systems framework, has resulted in the separation of public health functions and health-care services, which are interdependent in actuality and must be integrated to ensure a continuous, unbroken national health system.

Stephen S Morse

Memories of plagues remain with us. The 1918 influenza pandemic, one of the greatest natural disasters in history, the devastating effects of Ebola virus disease in 2014, the toll of the HIV/AIDS pandemic, and resonances of the medieval Black Death are among the reminders that infectious diseases still evoke powerful images and fear. As I write, an Ebola virus disease outbreak in Democratic Republic of the Congo is just winding down, and Nipah virus has appeared again in India, causing 17 deaths.

Alexander Kumar

I started my application to medical school by writing my belief that “every human being should have equal and fair access to adequate health care”. 18 years later and now a primary care academic clinical fellow, I stand by this belief. It was by no coincidence that the 1978 Declaration of Alma-Ata was signed at the International Conference on Primary Health Care. Global primary health care is key to unlocking inequality and inequity—it works not only to achieve the definition of health as physical, mental, and social wellbeing but also works to achieve family, community, and spiritual wellbeing.

Richard Lane

Although only a child at the time, Yelzhan Birtanov, Minister of Healthcare of Kazakhstan, remembers the landmark 1978 Alma-Ata conference. His physician parents were attendees. “I recall doing drawings with the pens that they brought back from the meeting, and looking at a lot of photos of the conference; even as a young child, it was clear that something major was taking place in my country”, he says.

Ursula Theuretzbacher, Simon Gottwalt, Peter Beyer, Mark Butler, Lloyd Czaplewski, Christian Lienhardt, Lorenzo Moja, Mical Paul, Sarah Paulin, John H Rex, Lynn L Silver, Melvin Spigelman, Guy E Thwaites, Jean-Pierre Paccaud, Stephan Harbarth

This analysis of the global clinical antibacterial pipeline was done in support of the Global Action Plan on Antimicrobial Resistance. The study analysed to what extent antibacterial and antimycobacterial drugs for systemic human use as well as oral non-systemic antibacterial drugs for Clostridium difficile infections were active against pathogens included in the WHO priority pathogen list and their innovativeness measured by their absence of cross-resistance (new class, target, mode of action).

Yibeltal Assefa, Dessalegn Tesfaye, Wim Van Damme, Peter S Hill

Weakness of primary health-care (PHC) systems has represented a challenge to the achievement of the targets of disease control programmes (DCPs) despite the availability of substantial development assistance for health, in resource-poor settings. Since 2005, Ethiopia has embraced a diagonal investment approach to strengthen its PHC systems and concurrently scale up DCPs. This approach has led to a substantial improvement in PHC-system capacity that has contributed to increased coverage of DCPs and improved health status, although gaps in equity and quality in health services remain to be addressed.

Thomas Hone, James Macinko, Christopher Millett

The Sustainable Development Goals (SDGs) are now steering the global health and development agendas. Notably, the SDGs contain no mention of primary health care, reflecting the disappointing implementation of the Alma-Ata declaration of 1978 over the past four decades. The draft Astana declaration (Alma-Ata 2·0), released in June, 2018, restates the key principles of primary health care and renews these as driving forces for achieving the SDGs, emphasising universal health coverage. We use accumulating evidence to show that countries that reoriente their health systems towards primary care are better placed to achieve the SDGs than those with hospital-focused systems or low investment in health.

Manfred S Green, James LeDuc, Daniel Cohen, David R Franz

Global terrorism is a rapidly growing threat to world security, and increases the risk of bioterrorism. In this Review, we discuss the potential threat of bioterrorism, agents that could be exploited, and recent developments in technologies and policy for detecting and controlling epidemics that have been initiated intentionally. The local and international response to infectious disease epidemics, such as the severe acute respiratory syndrome and west African Ebola virus epidemic, revealed serious shortcomings which bioterrorists might exploit when intentionally initiating an epidemic.

David A Watkins, Gavin Yamey, Marco Schäferhoff, Olusoji Adeyi, George Alleyne, Ala Alwan, Seth Berkley, Richard Feachem, Julio Frenk, Gargee Ghosh, Sue J Goldie, Yan Guo, Sanjeev Gupta, Felicia Knaul, Margaret Kruk, Rachel Nugent, Osondu Ogbuoji, Jinyuan Qi, Srinath Reddy, Helen Saxenian, Agnés Soucat, Dean T Jamison, Lawrence H Summers

In 2013, the Lancet Commission on Investing in Health published its report, “Global health 2035: a world converging within a generation” (GH2035). The report concluded that a grand convergence in health—a reduction in infectious, child, and maternal mortality to rates seen in the best-performing middle-income countries—is technically and financially feasible for all but the poorest countries by 2035. Mortality from non-communicable diseases could be reduced through inexpensive population-based and clinical interventions, especially fiscal policies such as heavy tobacco taxation.

Douglas G. Widman, Savanna Gornisiewicz, Sharon Shacham, Sharon Tamir

by Douglas G. Widman, Savanna Gornisiewicz, Sharon Shacham, Sharon Tamir Infection of immunocompromised individuals with normally benign opportunistic viruses is a major health burden globally. Infections with viruses such as Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), Kaposi’s sarcoma virus (KSHV), adenoviruses (AdV), BK virus (BKPyV), John Cunningham virus (JCPyV), and human papillomavirus (HPV) are significant concerns for the immunocompromised, including when these viruses exist as a co-infection with human immunodeficiency virus (HIV). These viral infections are more complicated in patients with a weakened immune system, and often manifest as malignancies resulting in significant morbidity and mortality. Vaccination is not an attractive option for these immune compromised individuals due to defects in their adaptive immune response. Verdinexor is part of a novel class of small molecules known as SINE (Selective Inhibitor of Nuclear Export) compounds. These small molecules demonstrate specificity for the nuclear export protein XPO1, to which they bind and block function, resulting in sequestration of XPO1-dependent proteins in the nucleus of the cell. In antiviral screening, verdinexor demonstrated varying levels of efficacy against all of the aforementioned viruses including previously with HIV. Studies by other labs have discussed likely mechanisms of action for verdinexor (ie. XPO1-dependence) against each virus. GLP toxicology studies suggest that anti-viral activity can be achieved at a tolerable dose range, based on the safety profile of a previous phase 1 clinical trial of verdinexor in healthy human volunteers. Taken together, these results indicate verdinexor has the potential to be a broad spectrum antiviral for immunocompromised subjects for which vaccination is a poor option.

Shilah A. Bonnett, Devon Dennison, Megan Files, Anumita Bajpai, Tanya Parish

by Shilah A. Bonnett, Devon Dennison, Megan Files, Anumita Bajpai, Tanya Parish There is an urgent need for the development of shorter, simpler and more tolerable drugs to treat antibiotic tolerant populations of Mycobacterium tuberculosis. We previously identified a series of hydrazones active against M. tuberculosis. We selected five representative compounds for further analysis. All compounds were active against non-replicating M. tuberculosis, with two compounds demonstrating greater activity under hypoxic conditions than aerobic culture. Compounds had bactericidal activity with MBC/MIC of < 4 and demonstrated an inoculum-dependent effect against aerobically replicating bacteria. Bacterial kill kinetics demonstrated a faster rate of kill against non-replicating bacilli generated by nutrient starvation. Compounds had limited activity against other bacterial species. In conclusion, we have demonstrated that hydrazones have some attractive properties in terms of their anti-tubercular activity.

Beernink P, Ispasanie E, Lewis L, et al.

AbstractBackgroundMeningococcal outer membrane vesicle (OMV) vaccines are prepared with detergents to remove endotoxin, which also removes desirable antigens such as Factor H binding protein (FHbp). Native OMV (NOMV) vaccines with genetically attenuated endotoxin do not require detergent treatment and elicit broader serum bactericidal antibody (SBA) responses than OMV or recombinant FHbp (rFHbp) vaccines.MethodsWe measured human complement-mediated SBA responses of mice immunized with NOMV with over-expressed FHbp sub-family B (NOMV-FHbp), NOMV with FHbp genetically inactivated (NOMV-KO) and/or a control rFHbp vaccine against meningococcal and gonococcal strains.ResultsDespite having 36-fold less FHbp per dose, the NOMV-FHbp vaccine elicited a ≥3-fold higher serum IgG anti-FHbp geometric mean titer than control vaccines containing FHbp (p≤0.003). Against two meningococcal outbreak strains with mismatched PorA and heterologous FHbp sub-family B sequence variants, the NOMV-FHbp vaccine produced ≥30-fold higher SBA titers than control vaccines. Mice immunized with NOMV-FHbp and NOMV-KO vaccines also elicited SBA against a gonococcal strain (p

Ravichandran, A., Geng, M., Hull, K. G., Li, J., Romo, D., Lu, S.-E., Albee, A., Nutter, C., Gordon, D. M., Ghannoum, M. A., Lockless, S. W., Smith, L.

Occidiofungin is produced by the soil bacterium Burkholderia contaminans MS14 likely as an antifungal agent. This study identified the primary cellular target of occidiofungin, which was determined to be actin. Occidiofungin modified with a functional alkyne group enabled affinity purification assays and localization studies in yeast. Occidiofungin has a subtle effect on actin dynamics that triggers an apoptotic cell death. We demonstrate highly specific localization of occidiofungin to cellular regions rich in actin in yeast and binding of occidiofungin to purified actin in vitro. Further, disruption of actin mediated cellular processes such as endocytosis, nuclear segregation, and hyphae formation were observed. All these processes require the formation of stable actin cables, which are disrupted following the addition of a subinhibitory concentration of occidiofungin. We were also able to demonstrate the effectiveness of occidiofungin in treating a vulvovaginal yeast infection in a murine model. The results of this study are important for the development of an efficacious novel class of actin binding drugs that could fill the existing gap in treatment options for fungal infections or in the treatment of different types of cancer.

Buss, J. A., Baidin, V., Welsh, M. A., Flores-Kim, J., Cho, H., Wood, B. M., Uehara, T., Walker, S., Kahne, D., Bernhardt, T. G.

New antibiotics are needed to combat the growing problem of resistant bacterial infections. An attractive avenue towards the discovery of such next generation therapies is to identify novel inhibitors of clinically validated targets like cell wall biogenesis. We have therefore developed a pathway-directed, whole-cell screen for small molecules that block the activity of the Rod system of Escherichia coli. This conserved multi-protein complex is required for cell elongation and the morphogenesis of rod-shaped bacteria. It is composed of cell wall synthases and membrane proteins of unknown function that are organized by filaments of the actin-like MreB protein. Our screen takes advantage of the conditional essentiality of the Rod system and the ability of the beta-lactam mecillinam to cause a toxic malfunctioning of the machinery. Rod system inhibitors can therefore be identified as molecules that promote growth in the presence of mecillinam under conditions permissive for the growth of Rod– cells. A screen of ~690,000 identified 1,300 compounds active against E. coli. Pathway-directed screening of a majority of this subset of compounds for Rod inhibitors successfully identified eight analogs of the MreB-antagonist A22. Further characterization of the A22 analogs identified showed that their antibiotic activity under conditions where the Rod system is essential was strongly correlated with their ability to suppress mecillinam toxicity. This result combined with additional biological studies reinforce the notion that A22-like molecules are relatively specific for MreB and suggest that the lipoprotein transport factor LolA is unlikely to be a physiologically relevant target as previously proposed.

Abstract Background Aerococcus urinae is a gram-positive, alpha-hemolytic coccus bacterium primarily implicated in less than 1 % of all symptomatic urinary tract infections. Risk factors for disease include male gender, advanced age, and comorbid genitourinary tract pathology. Infections beyond the genitourinary tract are rare, though spondylodiscitis, perineal abscesses, lymphadenitis, bacteremia, meningitis, and endocarditis have been reported. Less than fifty cases of A. urinae infective endocarditis (IE) have been described in the literature. The rare occurrence of A. urinae in human infections and resultant lack of randomized controlled trials have resulted in a significant degree of clinical uncertainty in the management of A. urinae IE. Case presentation We present an unusual case of a forty-three year-old male with A. urinae infective endocarditis (IE) who was successfully treated with mitral valve replacement and six weeks of penicillin/gentamicin therapy. In addition, we include a comprehensive review of all reported cases of IE due to A. urinae with specific attention to therapeutic regimens and treatment durations. Conclusion Recent advances in diagnostic technology have led to an increase in the frequency A. urinae is diagnosed. Reviewing cases of Aerococcus urinae infections, their clinical courses and subsequent management can assist future healthcare providers and their patients.

Abstract Background Plasmodium vivax is the most geographically widespread of the human malaria parasites, causing 50,000 to 100,000 deaths annually. Plasmodium vivax parasites have the unique feature of forming dormant liver stages (hypnozoites) that can reactivate weeks or months after a parasite-infected mosquito bite, leading to new symptomatic blood stage infections. Efforts to eliminate P. vivax malaria likely will need to target the persistent hypnozoites in the liver. Therefore, research on P. vivax liver stages necessitates a marker for clearly distinguishing between actively replicating parasites and dormant hypnozoites. Hypnozoites possess a densely fluorescent prominence in the parasitophorous vacuole membrane (PVM) when stained with antibodies against the PVM-resident protein Upregulated in Infectious Sporozoites 4 (PvUIS4), resulting in a key feature recognizable for quantification of hypnozoites. Thus, PvUIS4 staining, in combination with the characteristic small size of the parasite, is currently the only hypnozoite-specific morphological marker available. Results Here, the generation and validation of a recombinant monoclonal antibody against PvUIS4 (α-rUIS4 mAb) is described. The variable heavy and light chain domains of an α-PvUIS4 hybridoma were cloned into murine IgG1 and IgK expression vectors. These expression plasmids were co-transfected into HEK293 cells and mature IgG was purified from culture supernatants. It is shown that the α-rUIS4 mAb binds to its target with high affinity. It reliably stains the schizont PVM and the hypnozoite-specific PVM prominence, enabling the visual differentiation of hypnozoites from replicating liver stages by immunofluorescence assays in different in vitro settings, as well as in liver sections from P. vivax infected liver-chimeric mice. The antibody functions reliably against all four parasite isolates tested and will be an important tool in the identification of the elusive hypnozoite. Conclusions The α-rUIS4 mAb is a versatile tool for distinguishing replicating P. vivax liver stages from dormant hypnozoites, making it a valuable resource that can be deployed throughout laboratories worldwide.

Laure Stella Ghoma Linguissi, Violaine Lucaccioni, Matthew Bates, Alimuddin Zumla, Francine Ntoumi

Abstract Introduction The incidence of Acinetobacter baumannii meningitis, which typically occurs after neurosurgery, has increased in recent years. Pediatric Acinetobacter baumannii meningitis due to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains has important clinical significance. Methodology We retrospectively reviewed the clinical course and outcome of nine cases of meningitis due to Acinetobacter baumannii in children and reviewed the relevant literature. Results Seven patients had a history of neurosurgery, and the average time from the first surgery to cerebrospinal fluid (CSF) culture in these seven patients was 23.71 ± 17.43 days. Of all nine patients, four patients showed MDR isolates, two showed XDR isolates, and one showed pan-drug-resistant (PDR) isolates. Three patients received an intrathecal injection of amikacin. Two patients received intravenous colistin (5 mg/kg), and one received polymyxin B (2 mg/kg). The mean hospitalization duration was 39.44 days. Four patients eventually died: two with MDR Acinetobacter, one with PDR Acinetobacter, and one with susceptible Acinetobacter. Two of them still had positive CSF cultures at death. Conclusion Acinetobacter baumannii meningitis is usually associated with neurosurgery and the placement of foreign material, and it usually has a high mortality. Intrathecal or intraventricular polymyxin administration is expected to be an effective choice for meningitis but requires further study.

Poirel, L., Ortiz De La Rosa, J.-M., Kieffer, N., Dubois, V., Jayol, A., Nordmann, P.

A clinical Pseudomonas aeruginosa isolate resistant to all β-lactams including ceftolozane-tazobactam and carbapenems was recovered. It belonged to the Sequence Type ST235 and produced the extended-spectrum β-lactamase (ESBL) GES-6 differing from GES-1 by two amino-acid substitutions (E104K and G170S). GES-6 possessed an increased hydrolytic activity toward carbapenems and to ceftolozane, and a decreased susceptibility to β-lactamase inhibitors as compared to GES-1, except for avibactam. We showed here that resistance to ceftolozane-tazobactam may occur through acquisition of a specific ESBL in P. aeruginosa, but that ceftazidime-avibactam combination remained an effective alternative.

Melief, E., Bonnett, S. A., Zuniga, E. S., Parish, T.

The diaminoquinazoline series has good potency against Mycobacterium tuberculosis. Resistant isolates have mutations in Rv3161c, a putative dioxygenase. We carried out metabolite analysis on wild-type and an Rv3161c mutant strain after exposure to a diaminoquinazoline. The parental compound was found in intracellular extracts from the mutant, but not the wild-type. A metabolite consistent with a mono-hydroxylated form was identified in the wild-type. These data support the hypothesis that Rv3161c metabolizes diaminoquinazolines in M. tuberculosis.

Sabet, M., Tarazi, Z., Griffith, D. C.

We have evaluated the activity of meropenem-vaborbactam against clinical isolates of Pseudomonas aeruginosa and Acinetobacter baumannii in a neutropenic mouse thigh infection model. Data show that meropenem-vaborbactam regimens equivalent to 3-hour infusions every 8 hours with 2g meropenem-2g vaborbactam produced bacterial killing against strains with MICs of 2 – 16 mg/L and suggests that this combination may have utility in the treatment of infections caused by P. aeruginosa and A. baumannii.

Ranmini S. Kularatne, Ronelle Niit, Jane Rowley, Tendesayi Kufa-Chakezha, Remco P. H. Peters, Melanie M. Taylor, Leigh F. Johnson, Eline L. Korenromp

by Ranmini S. Kularatne, Ronelle Niit, Jane Rowley, Tendesayi Kufa-Chakezha, Remco P. H. Peters, Melanie M. Taylor, Leigh F. Johnson, Eline L. Korenromp Objectives To estimate trends in prevalence and incidence of syphilis, gonorrhea and chlamydia in adult men and women in South Africa. Methods The Spectrum-STI tool estimated trends in prevalence and incidence of active syphilis, gonorrhea and chlamydia, fitting South African prevalence data. Results were used, alongside programmatic surveillance data, to estimate trends in incident gonorrhea cases resistant to first-line treatment, and the reporting gap of symptomatic male gonorrhea and chlamydia cases treated but not reported as cases of urethritis syndrome. Results In 2017 adult (15–49 years) the estimated female and male prevalences for syphilis were 0.50% (95% CI: 0.32–0.80%) and 0.97% (0.19–2.28%), for gonorrhea 6.6% (3.8–10.8%) and 3.5% (1.7–6.1%), and for chlamydia 14.7% (9.9–21%) and 6.0% (3.8–10.4%), respectively. Between 1990 and 2017 the estimated prevalence of syphilis declined steadily in women and men, probably in part reflecting improved treatment coverage. For gonorrhea and chlamydia, estimated prevalence and incidence showed no consistent time trend in either women or men. Despite growing annual numbers of gonorrhea cases − reflecting population growth − the estimated number of first line treatment-resistant gonorrhea cases did not increase between 2008 and 2017, owing to changes in first-line antimicrobial treatment regimens for gonorrhea in 2008 and 2014/5. Case reporting completeness among treated male urethritis syndrome episodes was estimated at 10–28% in 2017. Conclusion South Africa continues to suffer a high STI burden. Improvements in access and quality of maternal, STI and HIV health care services likely contributed to the decline in syphilis prevalence. The lack of any decline in gonorrhea and chlamydia prevalence highlights the need to enhance STI services beyond clinic-based syndromic case management, to reinvigorate primary STI and HIV prevention and, especially for women, to screen for asymptomatic infections.

Abstract Background An estimated 30 million women give birth annually in malaria endemic areas of sub-Saharan Africa. Malaria in pregnancy is associated with an increased risk of adverse maternal and infant outcomes. To combat the adverse effects of MiP, the World Health Organization (WHO) recommends the provision of intermittent preventive treatment in pregnancy with sulfadoxine–pyrimethamine (IPTp–SP) in areas of moderate to high malaria transmission. In 2012, the WHO updated its policy with respect to IPTp administration to recommend administration at each antenatal care visit in the second and third trimesters, with a minimum of three, rather than two, doses. While rapid improvements in coverage were expected, gains have occurred more slowly than anticipated. Methods The President’s Malaria Initiative (PMI) assessed IPTp uptake before and after countries implemented the new WHO policy, and assessed how long it took for implementation to occur, using a combination of data from household surveys, routine health management information systems, and programmatic data provided to PMI. Results It took an average of 2 years for countries to complete the process of revising their IPTp policies, and it was not until 2015 that all 17 PMI countries had updated their policies. Policy dissemination and training had not been completed in several countries as of early 2018, and only seven countries had fully implemented the new policy including updating their antenatal care registers to collect information on IPTp3+ coverage. The coverage of IPTp1+, 2+, and 3+ has increased by 19, 16, and 13 percentage points since the revised IPTp policy adoption. Discussion Overall, coverage of both IPTp2+ and IPTp3+ has improved in recent years. The change in policy from a minimum of two to a minimum of three doses has likely contributed to these improvements. Progress has been slow, likely related to the complicated process of policy adoption exacerbated by the lag in measurement through national household surveys. The impact of future policy changes may be more readily seen if the policy change and implementation process were more streamlined and coordinated between key stakeholders (National Malaria Control Programmes and Reproductive Health Programmes), with more real-time data reporting.

Solomon Sisay, Ayehu Mekonen, Adugna Abera, Yifru Berhan, Tadele Kebede, Abebe Ferede

Globally, Human Immunodeficiency Virus (HIV) and Tuberculosis (TB) are one of the leading causes of death if they occurred as co-morbidity in affected individuals. Therefore, we aimed to evaluate the collaboration of TB and HIV control activities by determining the co-morbidity rate between 2009 and 2015 in Oromia Region, Ethiopia.

Abstract Malaria is a major cause of anaemia in tropical areas. Malaria infection causes haemolysis of infected and uninfected erythrocytes and bone marrow dyserythropoiesis which compromises rapid recovery from anaemia. In areas of high malaria transmission malaria nearly all infants and young children, and many older children and adults have a reduced haemoglobin concentration as a result. In these areas severe life-threatening malarial anaemia requiring blood transfusion in young children is a major cause of hospital admission, particularly during the rainy season months when malaria transmission is highest. In severe malaria, the mortality rises steeply below an admission haemoglobin of 3 g/dL, but it also increases with higher haemoglobin concentrations approaching the normal range. In the management of severe malaria transfusion thresholds remain uncertain. Prevention of malaria by vector control, deployment of insecticide-treated bed nets, prompt and accurate diagnosis of illness and appropriate use of effective anti-malarial drugs substantially reduces the burden of anaemia in tropical countries.

Yoon-Jung Kang, Megan Smith, Karen Canfell

by Yoon-Jung Kang, Megan Smith, Karen Canfell Background Previous studies have reported that anal cancer incidence has increased in individual countries; however, age-specific trends were not examined in detail. This study describes pooled and country-specific anal cancer incidence trends by sex, age (all ages,…

Choi Y, Zhang X, Skinner B.

AbstractBackgroundSecondary spread of hepatitis E virus (HEV) infection occurs often in endemic settings in developing countries. The host immune signatures contributing to protection against subsequent HEV reinfection are unknown.MethodsTwelve seroconverted rhesus macaques were re-inoculated with homologous HEV genotype 1 (gt1, Sar-55) and followed for 115 days. HEV RNA, HEV-specific T-cell responses, IgG anti-HEV antibody, and the IgG anti-HEV avidity index were tested.ResultsFour animals with baseline IgG anti-HEV levels from 1.5 to 13.4 WHO U/ml evidenced reinfection as determined by HEV RNA in stool, and increase in IgG anti-HEV levels between 63- and 285-fold (P= 0.003). Eight animals with baseline IgG anti-HEV levels from 2.8 to 90.7 WHO U/ml did not develop infection or shed virus in feces, and IgG anti-HEV antibody levels were unchanged (P= 0.017). The four reinfected animals showed a lower HEV-IgG avidity index (average 35.5%) than the 8 protected animals (average 62.1%). HEV-specific IFN- producing T cells were 2-fold higher in reinfected animals (P= 0.018).ConclusionsPre-existing antibody and high IgG avidity index (>50%) are important factors for protection against HEV reinfection. HEV-specific T cell responses were elevated in reinfected animals after subsequent exposure to HEV.

Esben Budtz-Jørgensen, Philippe Grandjean

by Esben Budtz-Jørgensen, Philippe Grandjean Background Developmental exposure to perfluorinated alkylate substances (PFASs) is associated with deficient IgG antibody responses to childhood vaccines. As this immunotoxicity outcome may represent a critical effect, calculation of benchmark dose (BMD) results would be useful for defining protective limits of exposure. However, exposures to the major PFASs that are associated with this adverse effect are interrelated, and mutually adjusted BMD results would be desirable. Methods We carried out BMD calculations on prospective data from two prospective birth cohort studies from the Faroe Islands with a total of 1,146 children. Exposure data included serum concentrations of five major PFASs at birth and at age 5 years and, as outcome parameters, the serum concentrations of specific IgG antibodies against tetanus and diphtheria at ages 5 and 7. We calculated the BMDs and their lower confidence bounds (BMDLs) and included mutual adjustment for five major PFASs. BMD and BMDL were expressed in terms of the serum concentration of the PFASs. Results The BMDLs for the immunotoxicants were of similar magnitude before and after adjustment. As compared to linear dose-response models, the PFASs showed lower results for a piecewise linear model, which also provided a slightly better fit. Weaker associations with the antibody outcomes were observed after adjustments due to the correlation between the PFASs. However, while the adjustments resulted in elevated BMD results and p values, the BMDL values were not materially changed. Conclusions Adjustment for co-exposure to a related immunotoxicant increased both the BMD values and their standard errors, though affected the BMDL values only to a negligible extent. Thus, when correlated toxicants appear to affect the same outcome and none of them is known a priori to be solely responsible, all exposures may be considered responsible in BMD calculations. Our BMDL results, both before and after adjustment are generally below current exposure levels and therefore suggest that all five perfluorinated substances should attract regulatory attention, at least until additional evidence shows otherwise.

Jacobs, M. R., Abdelhamed, A. M., Good, C. E., Rhoads, D. D., Hujer, K. M., Hujer, A. M., Domitrovic, T. N., Rudin, S. D., Richter, S. S., van Duin, D., Kreiswirth, B. N., Greco, C., Fouts, D. E., Bonomo, R. A., for the Antibacterial Resistance Leadership Group(ARLG)

Activity of the siderophore cephalosporin cefiderocol, targeted for activity against carbapenem resistant Gram-negatives, was determined by microdilution in iron-depleted Mueller Hinton broth against characterized carbapenem resistant Acinetobacter baumannii complex, Stenotrophomonas maltophilia, Pseudomonas aeruginosa and Enterobacteriaceae. MIC90s against A. baumannii, S. maltophilia and P. aeruginosa were 1, 0.25 and 0.5 mg/L, respectively. Against Enterobacteriaceae, MIC90 was 1 mg/L for OXA-48-like group, 2 mg/L for KPC-3 group, and 8 mg/L for TEM/SHV ESBL, NDM and KPC-2 groups.

Emer P. Reeves

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 8, Page 1099-1102, October 15, 2018.

Carlos Iniesta, Débora Álvarez-del Arco, Luis Miguel García-Sousa, Belén Alejos, Asunción Díaz, Nieves Sanz, Jorge Garrido, Michael Meulbroek, Ferran Pujol, Santiago Moreno, María José Fuster-Ruiz de Apocada, Pep Coll, Antonio Antela, Jorge del Romero, Oskar Ayerdi, Melchor Riera, Juanse Hernández, Julia del Amo

by Carlos Iniesta, Débora Álvarez-del Arco, Luis Miguel García-Sousa, Belén Alejos, Asunción Díaz, Nieves Sanz, Jorge Garrido, Michael Meulbroek, Ferran Pujol, Santiago Moreno, María José Fuster-Ruiz de Apocada, Pep Coll, Antonio Antela, Jorge del Romero, Oskar Ayerdi, Melchor Riera, Juanse Hernández, Julia del Amo Objective To assess the awareness, knowledge, use, and willingness to use and need of PrEP among men who have sex with men (MSM) and transgender women (TW) who attended World Gay Pride (WGP) 2017 in Madrid. Design and methods Online survey. Participants were recruited through gay-oriented dating apps and HIV Non-Governmental Organizations´ social media. Inclusion criteria included being MSM or TW, age 18 years old or above, and having attended WGP in Madrid. Information regarding the participant’s awareness and knowledge, use or willingness to use, and need for PrEP was collected, as well as sociodemographic characteristics. Participants were considered to be in need of PrEP if they met one of the following indication criteria: having practiced unprotected anal intercourse with more than 2 partners, having practiced chemsex, or having engaged in commercial sex—all in the preceding 6 months. Descriptive and multivariable analyses with logistic regression were conducted. Results 472 participants met the inclusion criteria and completed the questionnaire. The mean age was 38, 97.7% were MSM, 77% had a university education, and 85% were living in Spain, mostly in big cities. Overall, 64% of participants were aware of PrEP, but only 33% knew correctly what PrEP was. 67% of HIV-negative participants were willing to take PrEP, although only 5% were taking it during WGP, mostly due to lack of access. 43% of HIV-negative respondents met at least one PrEP indication criteria. For HIV-negative men living in Spain, university education and living in big cities was associated with PrEP awareness. Lower education level and meeting PrEP criteria was associated with willingness to use PrEP. Conclusions Our study shows that among MSM attending WGP 2017 in Madrid, there was limited PrEP awareness, low accuracy of PrEP knowledge, and a high need and willingness to use PrEP. Health authorities should strengthen existing preventive strategies and implement PrEP.

Tomoichiro Oka, Nobuhiro Iritani, Seiji P. Yamamoto, Kohji Mori, Tomoko Ogawa, Chika Tatsumi, Shinichiro Shibata, Seiya Harada, Fang‐Tzy Wu

Abstract Sapoviruses are associated with acute gastroenteritis. Human sapoviruses are classified into four distinct genogroups (GI, GII, GIV, and GV) based on their capsid gene sequences. A TaqMan probe based real‐time reverse transcription‐polymerase chain reaction (RT‐PCR) assay that detects representative strains of these four genogroups is widely used for screening fecal specimens, shellfish, and environmental water samples. However, since the development of this test, more genetically diverse sapovirus strains have been reported, and are not detected by the previously established assay. In this study, we report the development of a broader range sapovirus real‐time RT‐PCR assay. The assay can detect 2.5 × 107 and 2.5 × 101 copies of sapovirus, and therefore is as sensitive as the previous test. Analysis using clinical stool specimens or synthetic DNA revealed that the new system detected strains representative of all the 18 human sapovirus genotypes, GI.1‐7, GII.1‐8, GIV.1 and GV.1, 2; no cross‐reactivity was observed against other representative common enteric viruses (norovirus, rotavirus, astrovirus and adenovirus). This new assay will be useful as an improved broadly reactive and specific screening tool for human sapoviruses. This article is protected by copyright. All rights reserved.

Abstract Background Malaria rapid diagnostic tests (RDTs) available as dipsticks or strips, are simple to perform, easily interpretable and do not require electricity nor infrastructural investment. Correct interpretation of and compliance with the RDT results is a challenge to drug sellers. Thus, drug seller interpretation of RDT strips was compared with laboratory scientist re-reading, and PCR analysis of Plasmodium DNA extracted from RDT nitrocellulose strips and fast transient analysis (FTA) cards. Malaria RDT cassettes were also assessed as a potential source of Plasmodium DNA. Methods A total of 212 children aged between 2 and 60 months, 199 of whom had complete records at two study drug shops in south western Uganda participated in the study. Duplicate 5 μL samples of capillary blood were picked from the 212 children, dispensed onto the sample well of the CareStart™ Pf-HRP2 RDT cassette and a FTA, Whatman™ 3MM filter paper in parallel. The RDT strip was interpreted by the drug seller within 15–20 min, visually re-read centrally by laboratory scientist and from it; Plasmodium DNA was recovered and detected by PCR, and compared with FTA recovered P. falciparum DNA PCR detection. Results Malaria positive samples were 62/199 (31.2%, 95% CI 24.9, 38.3) by drug seller interpretation of RDT strip, 59/212 (27.8%, 95% CI 22.2, 34.3) by laboratory scientist, 55/212 (25.9%, 95% CI 20.0, 32.6) by RDT nitrocellulose strip PCR and 64/212 (30.2%, 95% CI 24.4, 37.7). The overall agreement between the drug seller interpretation and laboratory scientist re-reading of the RDT strip was 93.0% with kappa value of 0.84 (95% CI 0.75, 0.92). The drug seller compliance with the reported RDT results was 92.5%. The performance of the three diagnostic strategies compared with FTA-PCR as the gold standard had sensitivity between 76.6 and 86.9%, specificity above 90%, positive predictive values ranging from 79.0 to 89.8% and negative predictive values above 90%. Conclusion Drug sellers can use RDTs in field conditions and achieve acceptable accuracy for malaria diagnosis, and they comply with the RDT results. Plasmodium DNA can be recovered from RDT nitrocellulose strips even in the context of drug shops. Future malaria surveillance and diagnostic quality control studies with RDT cassette as a source of Plasmodium DNA are recommended.

E. Vonesh, K. L. Gooch, V. Khangulov, C. R. Schermer, K. M. Johnston, S. M. Szabo, J. S. Rumsfeld

by E. Vonesh, K. L. Gooch, V. Khangulov, C. R. Schermer, K. M. Johnston, S. M. Szabo, J. S. Rumsfeld For managing overactive bladder (OAB), mirabegron, a β3 adrenergic receptor agonist, is typically used as second-line pharmacotherapy after antimuscarinics. Therefore, patients initiating treatment with mirabegron and antimuscarinics may differ, potentially impacting associated clinical outcomes. When using observational data to evaluate real-world safety and effectiveness of OAB treatments, residual bias due to unmeasured confounding and/or confounding by indication are important considerations. Falsification analysis, in which clinically irrelevant endpoints are tested as a reference, can be used to assess residual bias. The objective in this study was to compare baseline cardiovascular risk among OAB patients by treatment, and assess the presence of residual bias via falsification analysis of OAB patients treated with mirabegron or antimuscarinics, to determine whether clinically relevant comparisons across groups would be feasible. Linked electronic health record and claims data (Optum/Humedica) for OAB patients in the United States from 2011–2015 were available, with index defined as first date of OAB treatment during this period. Unadjusted characteristics were compared across groups at index and propensity-matching conducted. Falsification endpoints (hepatitis C, shingles, community-acquired pneumonia) were compared between groups using odds ratios (ORs) and 95% confidence intervals (CI). The study identified 10,311 antimuscarinic- and 408 mirabegron-treated patients. Mirabegron patients were predominantly older males, with more comorbidities. The analytic sample included 1,188 antimuscarinic patients propensity-matched to 396 mirabegron patients; after matching, no significant baseline differences remained. Estimates of falsification ORs were 0.7 (CI:0.3–1.7) for shingles, 1.5 (CI:0.3–8.2) for hepatitis C, 0.8 (CI:0.4–1.8) and 0.9 (CI:0.6–1.4) for pneumonia. While propensity matching successfully balanced observed covariates, wide CIs prevented definitive conclusions regarding residual bias. Accordingly, further observational comparisons by treatment group were not pursued. In real-world analysis, bias-detection methods could not confirm that differences in cardiovascular risk in patients receiving mirabegron versus antimuscarinics were fully adjusted for, precluding clinically relevant comparisons across treatment groups.

Joseph A. Hippensteel

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 8, Page 981-983, October 15, 2018.

Wuerth, K., Lee, A. H. Y., Falsafi, R., Gill, E. E., Hancock, R. E. W.

Pseudomonas aeruginosa is an opportunistic pathogen that causes nosocomial pneumonia and infects patients with cystic fibrosis. P. aeruginosa lung infections are difficult to treat due to bacterial resistance to antibiotics, and strains with multi-drug resistance are becoming more prevalent. Here we examined the use of a small host defense peptide, innate defense regulator 1002 (IDR-1002), in an acute P. aeruginosa lung infection in vivo. IDR-1002 significantly reduced the bacterial burden in the bronchoalveolar lavage fluid (BALF) as well as MCP-1 in the BALF and serum, KC in the serum, and IL-6 in the BALF. RNA-Seq was conducted on lungs and whole blood and the effects of P. aeruginosa, IDR-1002, or the combination of P. aeruginosa and IDR-1002 were evaluated. Differential gene expression analysis showed that P. aeruginosa increased multiple inflammatory and innate immune pathways as well as affected hemostasis, matrix metalloproteinases, collagen biosynthesis, and various metabolism pathways in the lungs and/or blood. Infected mice treated with IDR-1002 had significant changes in gene expression compared to untreated infected mice, with fewer differentially expressed genes associated with the inflammatory and innate immune responses to microbial infection, and treatment also affected morphogenesis, certain metabolic pathways, and lymphocyte activation. Overall, these results show that IDR-1002 was effective in treating P. aeruginosa acute lung infections and associated inflammation.

Allan Coates

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 8, Page 988-990, October 15, 2018.

Gustavo A. Heresi

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 8, Page 1090-1093, October 15, 2018.

Abstract Chronic meningococcemia is defined by blood culture(s) positive for Neisseria meningitidis, symptoms duration > 7 days, and neither meningitis nor shock on admission. This series of 26 consecutive cases illustrates that this is a rare disease (

Jin, S., Huang, M., Kwon, Y., Zhang, L., Li, B.-W., Oh, S., Dong, J., Luo, D., Biswal, M., Cunning, B. V., Bakharev, P. V., Moon, I., Yoo, W. J., Camacho-Mojica, D. C., Kim, Y.-J., Lee, S. H., Wang, B., Seong, W. K., Saxena, M., Ding, F., Shin, H.-J., Ruoff, R. S.

Single-crystal metals have unique properties due to the absence of grain boundaries and strong anisotropy. Commercial single-crystal metals are usually synthesized by bulk crystal growth or by deposition of thin films onto substrates, and they are expensive and small. We prepare extremely large single-crystal metal foils by ‘contact-free annealing’ from commercial polycrystalline foils. The colossal grain growth (up to 32 cm2) is achieved by minimizing contact stresses, resulting in a preferred in-plane and out-of-plane crystal orientation, and is driven by surface energy minimization during the rotation of the crystal lattice followed by ‘consumption’ of neighboring grains. Industrial scale production of single-crystal metal foils is possible from this discovery.

Jason Rajchgot

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 8, Page 1105-1105, October 15, 2018.

Habib Hasan Farooqui, Sakthivel Selvaraj, Aashna Mehta, David L. Heymann

by Habib Hasan Farooqui, Sakthivel Selvaraj, Aashna Mehta, David L. Heymann India was the largest consumer of antibiotics in 2010 in the world. Evidence suggests that countries with high per-capita antibiotic consumption have higher rates of antibiotic resistance. To control antibiotic resistance, not only reduction in antibiotic consumption is required, socio-economic factors like access to clean water and sanitation, regulation of private healthcare sector and better governance are equally important. The key objective of this research was to investigate the five year trends in consumption of major antibiotic classes in India and compare them with European Surveillance of Antimicrobial Consumption Network (ESAC-Net) countries. We used Intercontinental Marketing Statistics (IMS) Health (now IQVIA) medicine sales audit data of antibiotic sales in the retail private sector (excluding the hospitals sector) in India. We then standardized dosage trends and assigned defined daily dose (DDD) to all formulations based on the ATC/DDD index. We expressed our data in standardized matrices of DDD per 1000 inhabitants’ per day (DID) to compare antibiotic use in India with ESAC-Net countries. The antibiotic use was plotted and reported by year and antibiotic class. Our main findings are—per capita antibiotic consumption in the retail sector in India has increased from 13.1 DID in 2008 to 16.0 DID in 2012—an increase of ~22%; use of newer class of antibiotics like carbapenems (J01DH), lincosamides (J01FF), glycopeptides (J01XA), 3rd generation cephalosporins (J01DD) and penicillin’s with beta-lactamase inhibitors has risen; and antibiotic consumption rates in India are still low as compared to ESAC-Net countries (16.0 DID vs. 21.54 DID). To conclude our study has provided the first reliable estimates of antibiotic use in the retail sector in India vis-à-vis ESAC-Net countries. In addition, our study could provide a reference point to measure the impact of interventions directed towards reducing antibiotic use.

Porter, A. M., Bland, C. M., Young, H. N., Allen, D. R., Croft, S. R., Gayheart, R. E., Miller, P. W., Musgrove, R. J., Robertson, E. M., Gibson, G. M.

Multiplex PCR combined with a pharmacist-driven reporting protocol was compared to standard-of-care within a community hospital to evaluate initial changes after notification of a positive blood culture. The intervention group demonstrated decreased time-to-change in antimicrobial therapy (p=0.0081), increased change to optimal antimicrobial therapy (p=0.013) and decreased vancomycin use for coagulase negative staphylococci contaminants (p

Girlich, D., Naas, T., Dortet, L.

The dissemination of carbapenemase-producing Enterobacteriaceae (CPE), has led to the increased use of colistin, which resulted in the emergence of colistin-resistant Enterobacteriaceae worldwide. One of the most threatening scenarios is the dissemination of colistin-resistance in CPE, particularly the plasmid-encoded resistance MCR. Thus, it becomes now mandatory to possess reliable media to screen for colistin-resistant Gram-negative isolates, especially Enterobacteriaceae. In this study we evaluated the performances of the Superpolymyxin™medium (ELITechGroup) and the CHROMID® Colistin R (bioMérieux) to screen for colistin-resistant Enterobacteriaceae from spiked rectal swabs. Stools were spiked with a total of 94 enterobacterial isolates (Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, Enterobacter cloacae), including 53 colistin-resistant isolates. ESwabs™(Copan Diagnostics) were then inoculated with those spiked fecal suspensions and proceed as recommended by both manufacturers. The sensitivity of detection colistin-resistant Enterobacteriaceae were of 86.8% [95% confidence interval (CI95) 74.0 – 94.0] using both the Superpolymyxin™medium and the CHROMID® Colistin R plates. Surprisingly, the isolates that were not detected were not the same for both media. The specificities were high for both media, at 97.9% [CI95 = 87.3% - 99.9%] for Superpolymyxin™medium and 100% [CI95 = 90.4% - 100%] for the CHROMID® Colistin R medium. Both commercially-available media, CHROMID® Colistin R and Superpolymyxin™, provide a useful tool to screen for colistin-resistant Enterobacteriaceae from patient samples (rectal swabs) regardless of the level and mechanism of colistin resistance.