M. Tchuenche, M. M. Gill, L. Bollinger, L. Mofenson, M. Phalatse, M. Nchephe, M. Mokone, V. Tukei, A. Tiam, S. Forsythe

by M. Tchuenche, M. M. Gill, L. Bollinger, L. Mofenson, M. Phalatse, M. Nchephe, M. Mokone, V. Tukei, A. Tiam, S. Forsythe Background Infants with HIV infection, particularly those infected in utero, who do not receive antiretroviral therapy (ART) have high mortality in the first year of life. Virologic diagnostic testing is recommended by the World Health Organization between ages 4 and 6 weeks after birth. However, adding very early infant diagnosis (VEID) testing at birth has been suggested to enable earlier diagnosis and rapid treatment of in utero infection. We assessed the costs of adding VEID to the standard 6-week testing in Lesotho where coverage of PMTCT services is nearly universal. Methods Retrospective cost data were collected at eight health-care facilities in three districts participating in an observational prospective study that included birth testing as well as at the National Reference Laboratory in Lesotho, to investigate the cost-per-infection identified. Extrapolating to the national level, it was possible to estimate the impact of VEID on the identification of HIV-infected infants. Results The unit cost-per-VEID test in Lesotho in 2015 was $40.50. Major cost drivers were supplies/commodities (46%) and clinical labor (22%). In 2015, 66.3% of cohort study infants born at study facilities underwent VEID; one out of 199 infants had a positive HIV DNA PCR test at birth (0.5% potential in utero infection), yielding a cost of $8,060 per HIV-positive infant identified. Sensitivity analysis showed costs based on Lesotho costing data ranged from $810 to $16,194 per-infected child with varying in utero infection rates from 5% and 0.25%, respectively. With 11,157 HIV-exposed births nationally from pregnant women on PMTCT, 66.3% VEID coverage, and 0.5% in utero infection, 37 infants infected with HIV could have been identified at birth in 2015 and 8 early infant deaths potentially averted with immediate ART compared with waiting for 6-week testing. Conclusion If Lesotho costing data from this pilot study were applied to different epidemic circumstances, the cost-per-infected child identified by adding VEID birth testing to standard 6-week testing was lowest when in utero infection rates were high (when HIV prevalence is high and PMTCT coverage is low).

Wang, D., Kong, L., Fan, P., Chen, H., Zhu, S., Liu, W., Cao, L., Sun, Y., Du, S., Schneeloch, J., Zhong, R., Gu, G., Fu, L., Ding, H., Gao, H.-J.

The search for Majorana bound states (MBSs) has been fueled by the prospect of using their non-Abelian statistics for robust quantum computation. Two-dimensional superconducting topological materials have been predicted to host MBSs as zero-energy modes in vortex cores. By using scanning tunneling spectroscopy on the superconducting Dirac surface state of the iron-based superconductor FeTe0.55Se0.45, we observe a sharp zero-bias peak inside a vortex core that does not split when moving away from the vortex center. The evolution of the peak under varying magnetic field, temperature, and tunneling barrier is consistent with the tunneling to a nearly pure MBS, separated from non-topological bound states. This observation offers a potential platform for realizing and manipulating MBSs at a relatively high temperature.

Abstract Background Post cardiac surgery mediastinitis is the major infectious complication, despite the development of surgical techniques and the application of strict preventive measures. The Haemophilus influenzae mediastinitis is very rare. The mediastinitis caused by the association between Haemophilus influenzae and Aggregatibacter aphrophilus has never been described to our knowledge. Case presentation We report the case of an exceptional combination of Haemophilus influenzae and Aggregatibacter aphrophilus in a patient operated for single bypass which is complicated by mediastinitis the 10th day after the surgical act. Conclusion The conclusion to be drawn from this work is to think in unusual seeds in case of mediastinitis post cardiac surgery for the elaboration of recommendations for antibiotic prophylaxis.

Shawn D. Aaron

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 4, Page 415-416, August 15, 2018.

Lubkin, David T.; Bishawi, Muath; Barbas, Andrew S.; Brennan, Todd V.; Kirk, Allan D.

Objectives: Extracellular mitochondrial DNA and N-formyl peptides released following tissue damage may contribute to systemic inflammation through stimulation of the innate immune system. In this review, we evaluate existing in vivo human data regarding a role for mitochondrial DNA and N-formyl peptides in producing systemic inflammation in trauma and critical illness, investigate the utility of these molecules in risk prediction and clinical decision support, and provide suggestions for standardization of future research. Data Sources: PubMed, Embase (1971–2017). Study Selection: Studies measuring extracellular mitochondrial DNA and/or N-formyl peptides in acutely ill patients. Data Extraction: Fifty-four studies were analyzed. Data extracted included article characteristics, methods, results, and performance in clinical prediction. Data Synthesis: The most common patient types investigated were trauma (19 studies) and sepsis (eight). In studies comparing patient mitochondrial DNA or N-formyl peptide levels to healthy controls, 38 (90.5%) reported significantly elevated mitochondrial DNA levels in patients at first reported time point, as did the one study making this comparison for N-formyl peptides. Nine studies (81.8%) reported significantly elevated plasma/serum mitochondrial DNA levels in at least one time point in patients who developed inflammatory complications of their primary pathology compared with patients without inflammatory complications. For the ability of mitochondrial DNA to predict complications or outcomes, the area under the curve was 0.7 or greater in 84.6% of receiver operating characteristic curves, and 92.9% of odds, adjusted odds, risk, and hazard ratios were statistically significant. Conclusions: Extracellular mitochondrial DNA levels are elevated early in patients’ hospital courses in many acute illnesses and are higher in patients who develop inflammatory complications. Elevated mitochondrial DNA levels may be clinically useful in risk prediction and clinical decision support systems. Further research is needed to determine the role of extracellular N-formyl peptides in systemic inflammation and their possible clinical utility. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by grant HT9404-13-1-0032 (to Dr. Kirk) from the Department of Defense. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Allan.Kirk@Duke.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Jean‐Louis Koulidiati , M. De Allegri , A. Souares , S. Ouedraogo , H. Hien , P. J. Robyn , S. Brenner

Abstract Objective To identify factors associated with both crude and effective health service coverage of under‐fives in rural Burkina Faso. Methods In a cross‐sectional study, 494 first‐line health facilities, 7,347 households and 12,497 under‐fives were surveyed. Two sequential logistic random effects models were conducted to assess factors associated with crude and effective coverage. Results Of 614 children under five with a reported illness episode, 427 (69.5%) received care at a health facility. Of those, 274 (64.1%) received care at a health facility providing at least the minimum threshold of service quality. We found that younger age, having a severe illness, shorter distance between household and health facility, and being from wealthier households were positively associated with crude coverage. In addition, low patient caseload and longer consultation had a positive association, while frequent facility supervisions had a negative association with effective coverage. Moreover the nurse to clinical staff ratio at the health facility was positively associated with both crude and effective coverage. Conclusion Our study found that crude coverage is associated with predisposing and enabling factors of health care access, while the availability of nurses is a strong predictor for both crude and effective coverage. This suggests that in the context of scarcity of resources, investing in human resources in health sector could be one of the priorities for decision‐makers to ensure children in need not only access to healthcare but also good quality of care. This article is protected by copyright. All rights reserved.

Kuehn B.

Clinicians are being urged to monitor patients after platelet transfusion for signs of bacterial infection after 2 separate US outbreaks linked to these blood products led to serious illnesses and deaths.

Abstract Purpose We report on a kidney transplant recipient treated with fecal microbiota transplantation (FMT) for recurrent urinary tract infections. Methods FMT was administered via frozen capsulized microbiota. Before and after FMT, urinary, fecal and vaginal microbiota compositions were analyzed. Results The patient remained without symptoms after FMT. Conclusions Underlying mechanisms of action need to be addressed in depth by future research.

G. Dubourg et al.

Hung, C.-Y., Zhang, H., Castro-Lopez, N., Ostroff, G. R., Khoshlenar, P., Abraham, A., Cole, G. T., Negron, A., Forsthuber, T., Peng, T., Galgiani, J. N., Ampel, N. M., Yu, J.-J.

Developing an effective and safe recombinant vaccine requires microbe-specific antigens combined with an adjuvant/delivery system to strengthen protective immunity. In this study, we designed and expressed a multivalent, recombinant Coccidioides polypeptide antigen (rCpa1) that consists of three previously identified antigens (i.e., Ag2/Pra, Cs-Ag and Pmp1) and 5 pathogen-derived peptides with high affinity for human MHC II molecules. The purified rCpa1 was encapsulated into four types of yeast cell-wall particles containing various compositions of β-glucan, mannan and chitin or mixed with an oligonucleotide (ODN) containing 2 methylated dinucleotide CpG motifs. This multivalent antigen encapsulated into glucan-chitin particles (GCP-rCpa1) showed a significantly elevated reduction of fungal burden for human HLA-DR4 transgenic mice compared to the other tested adjuvant-rCpa1 formulations. Among the tested adjuvants GCPs and GPs were both capable of stimulating a mixed Th1 and Th17 response. Mice vaccinated with GCP-rCpa1 showed elevated IL-17 production in T-cell recall assays and early lung infiltration of activated Th1 and Th17 cells compared to GP-rCpa1-vaccinated mice. Both C57BL/6 and HLA-DR4 transgenic mice that were vaccinated with GCP-rCpa1 vaccine increased surivial compared to the mice received GCPs alone. Concurringly, GCP-rCpa1 vaccine stimulated enhanced infiltration of macrophages to engulf and process the vaccine for antigen presentation in the injection sites compared to GP-rCpa1 injection. This is the first attempt to systematically characterize the presentation of a multivalent coccidioidomycosis vaccine encapsulated with selected adjuvants which enhance protective cellular immune response to infection.

Abstract Background Helcococcus ovis, belonging to the genus of Helcococcu in Peptostreptococcaceae, is one kind of facultative anaerobic and gram-positive cocci, which was first isolated from a mixed infection in sheep in 1999. To our knowledge, it’s known as an invasive pathogen in animals, and never been reported as a human pathogen in published literature. The aims of this work are to describe the first report of H. ovis which was recovered from the artificial eye of human case and perform a literature review. Case presentation A 26 year-old man reporting pyogenic infection with an artificial eye attended ophthalmic ward in Tongji hospital. After physical examination, clinical and laboratory investigations, the diagnosis of eye infection caused by Helcococcus ovis and Staphylococcus aureus was established. Receiving a medico-surgical approach, the patient was successfully treated. The treatment consisted in intravenous cefotaxime and ornidazole, levofloxacin eye drops during two weeks and removing of right artificial eye with debridement. Conclusions We describe here the first known case of H. ovis which was recovered from human artificial eye. This report different from previous data found in the literature emphasizes the invasive potential of this bacterial species as a pathogen in human. Prospectively, the application of next generation sequencing tools would contribute to a more accurate classification of clinical strains.

Maddalena Teggia Droghi

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 4, Page 524-525, August 15, 2018.

MohamedHashem , HassanZaghla , ZainabZakaria , Walaa R.Allam , Eman AbdelSameea , Nabiel N.Mikhail , MahaSobhy , Iman F.Galal , YasserMokhtar , ShimaaHamdy , GehanGalal , Sayed F.Abdelwahab , ImamWaked

Acute hepatitis C (AHC) infection resolves spontaneously in 15% to 40% of patients. Factors favoring spontaneous viral clearance remain undefined. In this study, predictors of spontaneous viral clearance in patients with symptomatic AHC were investigated. Epidemiological, clinical, and virologic parameters were also examined. Patients with symptomatic AHC were enrolled and followed up prospectively. The patients were followed up every 2 weeks in the first month and then monthly for the following 5 months, with a follow‐up visit 6 months after the last hepatitis C virus (HCV)‐RNA negative sample for those who had cleared the virus. Interleukin (IL)‐28B.rs12979860 single‐nucleotide polymorphism and HCV genotype were tested at baseline. HCV‐RNA was tested during each visit. Patients who remained RNA‐positive at 24 weeks were treated with pegylated interferon plus ribavirin for 24 weeks. A total of 30 patients, mostly with iatrogenically acquired AHC genotype 4 infections completed 6‐months’ follow‐up, to either spontaneous clearance or start of treatment. The mean age of the patients was 37 ± 13 years. In total, 67% of patients were females, and the mean incubation period was 7.6 ± 3.5 weeks. Viral clearance occurred spontaneously in 19 (63.3%) patients. The average time to clearance was 24.3 ± 9.6 weeks. A total of 11 patients received therapy, and 8 (72.7%) cleared the virus and had a sustained virologic response to the treatment 24 weeks after the therapy. A total of three patients were treatment nonresponders. IL28B.rs12979860 CC genotype, female gender, and viremia level were not associated with self‐limiting AHC in this cohort. In conclusion, patients with symptomatic AHC genotype 4 infection caused by an iatrogenic exposure had higher rates of spontaneous resolution than previously reported. Predicting spontaneous viral clearance after iatrogenic AHC exposure was not possible in this population.

Batugedara, H. M., Argueta, D., Jang, J. C., Lu, D., Macchietto, M., Kaur, J., Ge, S., Dillman, A. R., DiPatrizio, N. V., Nair, M. G.

Helminths have co-evolved with their hosts resulting in the development of specialized host immune mechanisms and parasite-specific regulatory products. Identification of new pathways that regulate helminth infection could provide a better understanding of host-helminth interaction and may identify new therapeutic targets for helminth infection. Here we identify the endocannabinoid system as a new mechanism that influences host immunity to helminths. Endocannabinoids are lipid-derived signaling molecules that control important physiologic processes such as feeding behavior and metabolism. Following murine infection with Nippostrongylus brasiliensisis (Nb), an intestinal nematode with a similar life cycle to hookworms, we observed increased levels of endocannabinoids (2-AG, AEA) and the endocannabinoid-like molecule OEA in the infected lung and intestine. To investigate endocannabinoid function in helminth infection, we employed pharmacological inhibitors of cannabinoid subtype receptor 1 and 2 (CB1R and CB2R). Compared to vehicle-treated mice, inhibition of CB1R but not CB2R resulted in increased Nb worm burden and egg output, associated with significantly decreased expression of T helper type 2 cytokine IL-5 in intestinal tissue and splenocyte cultures. Strikingly, bioinformatic analysis of genomic and RNA-seq datasets identified putative genes encoding endocannabinoid biosynthetic and degradative enzymes in many parasitic nematodes. To test the novel hypothesis that helminth parasites produce their own endocannabinoids, we measured endocannabinoid levels in Nb by mass spectrometry and quantitative PCR and found that Nb parasites produced endocannabinoids, especially at the infectious larval stage. To our knowledge, this is the first report of helminth and host-derived endocannabinoids that promote host immune responses and reduce parasite burden.

Abstract Background House improvement and environmental management can significantly improve malaria transmission control in endemic communities. This study assessed the influence of physical characteristics of houses and surrounding environments on mosquito biting risk in rural Tanzanian villages, and examined knowledge and perceptions of residents on relationships between these factors and malaria transmission. The study further assessed whether people worried about these risks and how they coped. Methods Entomological surveys of indoor mosquito densities were conducted across four villages in Ulanga district, south-eastern Tanzania. The survey involved 48 sentinel houses sampled monthly and other sets of 48 houses randomly recruited each month for one-off sampling over 12 months. Physical characteristics of the houses and surrounding environments were recorded. Questionnaire surveys were administered to 200 household heads to assess their knowledge and concerns regarding the observed housing and environmental features, and whether they considered these features when constructing houses. Focus group discussions, were conducted to clarify emergent themes on people’s perceptions on relationships between housing or environmental factors and malaria transmission. Results The entomological surveys showed statistically higher indoor densities of the malaria vectors (Anopheles arabiensis and Anopheles funestus) in houses with mud walls compared to plastered or brick walls, open eaves compared to closed eaves and unscreened windows compared to screened windows. Most respondents reported that their houses allowed mosquito entry, at least partially. Participants were aware that house structure and environmental characteristics influenced indoor mosquito densities and consequently malaria transmission. They were concerned about living in poorly-constructed houses with gaps on eaves, walls, windows and doors but were constrained by low income. Conclusion In rural south-eastern Tanzania, significant proportions of people still live in houses with open eaves, unscreened windows and gaps on doors. Though they are fully aware of associated mosquito biting and pathogen transmission risks, they are constrained by low-income levels. The study proposes that community-based house improvement initiatives combined with targeted subsidies could lower the financial barriers, improve access to essential construction materials or designs, and significantly accelerate malaria transmission control in these communities.

Alpha Oumar II Diallo, Véronique Chevalier, Julien Cappelle, Veasna Duong, Didier Fontenille, Raphaël Duboz

by Alpha Oumar II Diallo, Véronique Chevalier, Julien Cappelle, Veasna Duong, Didier Fontenille, Raphaël Duboz Japanese Encephalitis (JE) is the most important cause of human encephalitis throughout Asia and the Pacific. Although JE is a vector-borne disease, it has been demonstrated experimentally that transmission between pigs can occur through direct contact. Whether pig-to-pig transmission plays a role in the natural epidemiological cycle of JE remains unknown. To assess whether direct transmission between pigs may occur under field conditions, we built two mathematical models of JE transmission incorporating vector-borne transmission alone or a combination of vector-borne and direct transmission. We used Markov Chain Monte Carlo (MCMC) techniques to estimate the parameters of the models. We fitted the models to (i) two serological datasets collected longitudinally from two pig cohorts (C1 and C2) during two periods of four months on a farm on the outskirts of Phnom-Penh, Cambodia and to (ii) a cross-sectional (CS) serological survey dataset collected from 505 swine coming from eight different provinces of Cambodia. In both cases, the model incorporating both vector-borne and direct transmission better explained the data. We computed the value of the basic reproduction number R0 (2.93 for C1, 2.66 for C2 and 2.27 for CS), as well as the vector-borne reproduction number Rpv and the direct transmission reproduction number Rpp. We then determined the contribution of direct transmission on R0 (11.90% for C1, 11.62% for C2 and 7.51% for CS). According to our results, the existence of pig-to-pig transmission is consistent with our swine serological data. Thus, direct transmission may contribute to the epidemiological cycle of JE in Cambodia. These results need to be confirmed in other eco-climatic settings, in particular in temperate areas where pig-to-pig transmission may facilitate the persistence of JE virus (JEV) during cold seasons when there are no or few mosquitoes.

Showler, Adrienne J.; Nutman, Thomas B.

Purpose of review With increasing international travel and mass global population migration, clinicians in nonendemic countries must be familiar with imported neglected tropical diseases including onchocerciasis, which is commonly known as ‘river blindness’. Recent findings Imported onchocerciasis manifests differently in travelers compared with migrants from endemic areas and is likely underdiagnosed in both groups. Recent clinical studies confirm that eosinophilia is not a sensitive marker for Onchocerca volvulus, with one-third of patients having a normal eosinophil count. Novel diagnostics measuring antibodies to multiple recombinant O. volvulus antigens maintain a high sensitivity while improving specificity compared with conventional pan-filarial serologic testing. A 6-week course of doxycycline has macrofilaricidal activity through Wolbachia depletion and may be useful in nonendemic areas in addition to standard serial ivermectin. Summary Recent studies characterizing distinct clinical presentations in travelers and migrants may enable clinicians to better recognize imported onchocerciasis. Although novel diagnostics have improved specificity, most remain restricted to tropical disease reference laboratories and to date there is no marker of cure. Prolonged doxycycline treatment may reduce the need for serial ivermectin, though more potent short-course macrofilaricidal drugs are being developed. Correspondence to: Dr Thomas B. Nutman, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Tel: +1-301- 496- 5399; e-mail: tnutman@niaid.nih.gov Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Francesco Bisognin, Giulia Lombardi, Donatella Lombardo, Maria Carla Re, Paola Dal Monte

by Francesco Bisognin, Giulia Lombardi, Donatella Lombardo, Maria Carla Re, Paola Dal Monte Background The new Xpert MTB/RIF Ultra assay (Ultra, Cepheid, Sunnyvale, USA) is a cartridge-based automated diagnostic test that can simultaneously identify Mycobacterium tuberculosis complex (MTB) and resistance to Rifampicin (RIF). With respect to the previous version Xpert MTB/RIF assay (Xpert), IS6110/IS1081 repetitive elements probes have been added allowing the detection of lower MTB load, defined by the new semi-quantitative category “trace” with indeterminate RIF resistance. The aim of this study was to evaluate performance of the new version Ultra on Xpert-negative, but TB culture-positive clinical samples. Methods The de-identified frozen samples (-20 °C) collected over a 4-year period (February 2014-October 2017), which had previously resulted smear-negative, Xpert-negative but MTB culture-positive, were analyzed with Ultra. The de-frosted samples were loaded into the cartridge using the same process as the previous version, according to manufacturer’s instruction. Results During the study period 382 MTB culture-positive samples were archived: 314 resulted Xpert-positive and 68 Xpert-negative. Thirty-one of the 68 Xpert-negative samples resulted positive with Ultra, with an overall improvement in MTB detection of 45.6%. Out of 36 Xpert-negative respiratory samples, 18 resulted Ultra-positive with the following semi-quantitative loads: “low”(n = 1), “very low”(n = 11), “trace”(n = 6), with an improvement in MTB detection of 50%. The best performance was achieved on bronchoalveolar lavage specimens (53.8%). Out of 32 Xpert-negative non-respiratory samples, 13 resulted Ultra-positive with the following semi-quantitative loads: “very low”(n = 7), “trace”(n = 6), with an improvement in MTB detection of 40.6%. The best performance was achieved on biopsies (55.6%) and lymph nodes (50%). The new category “trace” detected 12 out of the 31 Ultra-positive MTB samples; in the remaining 19 samples RIF susceptibility was determined with 100% concordance with the phenotypic susceptibility test. The mean time to positivity of samples found negative by Ultra was significantly longer in comparison to positive samples in liquid culture. Conclusions Our results are consistent with the few studies published so far and confirm the better performance of Ultra compared to the previous version in both respiratory and non-respiratory smear-negative samples, with an overall improvement of 45.6%.

Xue, G., Crabb, D. M., Xiao, L., Liu, Y., Waites, K. B.

Levonadifloxacin (WCK 771) was evaluated against 68 type strains and clinical isolates of Mycoplasma genitalium, Mycoplasma hominis, Mycoplasma pneumoniae and Ureaplasma species in comparison to moxifloxacin, levofloxacin, tetracycline and azithromycin or clindamycin. Levonadifloxacin MICs were ≤ 0.5 μg/ml for Mycoplasma genitalium. MIC90s (μg/ml) were 1 (Mycoplasma hominis), 0.125 (Mycoplasma pneumoniae) and 2 (Ureaplasma spp). Levonadifloxacin merits further study for treating infections caused by these organisms.

Wiederhold, N. P., Xu, X., Wang, A., Najvar, L. K., Garvey, E. P., Ottinger, E. A., Alimardanov, A., Cradock, J., Behnke, M., Hoekstra, W. J., Brand, S. R., Schotzinger, R. J., Jaramillo, R., Olivo, M., Kirkpatrick, W. R., Patterson, T. F.

VT-1129 is a novel fungal-specific Cyp51 inhibitor with potent cryptococcal activity. Because of its long half-life (>6 days in mice) and the desire to quickly reach potent efficacy, we evaluated a VT-1129 loading dose-maintenance dose (LD-MD) strategy against cryptococcal meningitis. VT-1129 plasma and brain pharmacokinetics were first studied in healthy mice, and these data were used to model LD-MD doses to generate different steady-state concentrations. Mice were inoculated intracranially with C. neoformans, and oral treatment began 1 day later. Treatment consisted of placebo, three VT-1129 LD-MD groups: LD of 1, 3, or 30 mg/kg on day 1, followed by MD of 0.15, 0.5, or 5 mg/kg once daily, respectively. In the fungal burden arm, therapy continued for 14 days, and brains were collected on day 15 for fungal burden assessment. In the survival arm, treatment continued for 10 days after which mice were monitored off-therapy until day 30. VT-1129 plasma and brain concentrations were also measured. Each VT-1129 dose significantly improved survival and reduced fungal burden compared to placebo. VT-1129 plasma and brain levels correlated with fungal burden reductions (R2 = 0.72 and 0.67, respectively), with plasma concentration of 1 μg/mL yielding a reduction of ~5 log10 CFU/g. With the highest LD-MD dose, fungal burden was undetectable in half of the mice in the fungal burden arm, and in a quarter of the mice in the survival arm, 20 days after final dose. These data support an LD-MD strategy for quickly reaching highly efficacious VT-1129 concentrations in treating cryptococcal meningitis.

Morrison, H. A., Lowe, D., Robbins, J. R., Bakardjiev, A. I.

Listeria monocytogenes is a foodborne pathogen that infects the placenta and can cause pregnancy complications. Listeriosis infections usually occur as sporadic infections, but large outbreaks are also reported. Virulence from clinical isolates is rarely analyzed due to the large number of animals required, but this knowledge could help guide the response to an outbreak. We implemented a DNA barcode system using signature tags that allowed us to efficiently assay variations in virulence across a large number of isolates. We tested 77 signature-tagged clones of clinical L. monocytogenes strains from 72 infected human placentas and five immunocompromised patients, all isolated since 2000. These strains were tested for virulence in a modified competition assay in comparison to the laboratory strain 10403S. We used two in vivo models of listeriosis: the non-pregnant mouse and the pregnant guinea pig. Strains that were frequently found at high abundance within infected organs were considered "hypervirulent," while strains frequently found at low abundance were considered "hypovirulent." Virulence split relatively evenly among hypovirulent, hypervirulent, and strains equally virulent to 10403S. The laboratory strain was found to have an intermediate virulence phenotype, supporting its suitability for pathogenesis studies. Further, we found that splenic and placental virulence are closely linked in both guinea pig and mouse models. This suggests that outbreak and sporadic pregnancy-associated L. monocytogenes are not generally more virulent than lab reference strains. However, some strains did show consistent and reproducible virulence differences, suggesting that their further study may reveal deeper insights into the biological underpinnings of listeriosis.

Tom H Boyles, Rulan Griesel, Annemie Stewart, Marc Mendelson, Gary Maartens

Mawuli Dzodzomenyo, Anita Ghansah, Nana Ensaw, Benjamin Dovie, Langbong Bimi, Reginald Quansah, Ben A. Gyan, Mawuli Gyakobo, Benjamin Amoani

by Mawuli Dzodzomenyo, Anita Ghansah, Nana Ensaw, Benjamin Dovie, Langbong Bimi, Reginald Quansah, Ben A. Gyan, Mawuli Gyakobo, Benjamin Amoani Objective We assessed the association of mutant allele frequencies of nitric oxide synthase 2 (NOS2) gene at two SNPs (-954 and -1173) with malaria disease severity in children from a malaria endemic area in Southern Ghana. Method Using children recruited at the hospital, assigned into clinical subgroups of uncomplicated and severe malaria and matching with their “healthy control” counterparts, we designed a case control study. Genomic DNA was extracted and genotyping using Restriction Fragment Polymorphism was done. Result A total of 123 malaria cases (91 uncomplicated, 32 severe) and 100 controls were sampled. Their corresponding mean Hbs were 9.6, 9.3 and 11.2g/dl and geometric mean parasite densities of 32097, 193252 and 0 parasites/ml respectively. Variant allele frequencies varied from 0.09 through 0.03 to 0.12 for G-954C and 0.06 through 0.03 to 0.07 for C-1173T in the uncomplicated, severe and healthy control groups respectively. There was a strong linkage disequilibrium between the two alleles (p

Abstract Purpose Involvement of infectious disease (ID) specialists in the care of hospitalized patients with infections through consultation services improves the quality of care and the outcome of patients. This survey aimed to describe activities and utilization of ID consultations at four German tertiary care hospitals. Methods A 1-month (March 2016) retrospective cross-sectional study at four university hospitals (Freiburg, Jena, Cologne and Regensburg) was performed. Only ID consultations with written documentation and bedside patient evaluation were included. Consultations were analyzed with regard to requesting departments, infections, case severity, and diagnostic and therapeutic recommendations. Results In the study period, 638 ID consultations were performed in 479 patients—corresponding to 3–4 consultations per 100 inpatient cases. Patients were characterized by a high disease complexity—the mean case mix index in patients with consultation was 10.1 compared to 1.6 for all patients. ID consultations were requested by many different specialties, with approximately half of the requests coming from surgical disciplines. ID consultations resulted in revised diagnoses in 34% of the cases, provided recommendations for additional diagnostic procedures in 66%, and for modifications of antimicrobial regimens in 70% of the cases. Conclusions Infectious disease consultations were requested for patients with severe and complicated diseases and resulted in recommendations that highly impacted the diagnostic work-up and therapeutic management of patients. The results of this survey may help to estimate requirements for establishment of such services in Germany.

M. Bradley Drummond

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 4, Page 545-546, August 15, 2018.

Emelia T. Mwakanyanga, Golden M. Masika, Edith A. M. Tarimo

by Emelia T. Mwakanyanga, Golden M. Masika, Edith A. M. Tarimo Introduction Endotracheal suction (ETS) is a common invasive procedure which is done to keep the airways patent by mechanically removing accumulated pulmonary secretions to all in patients with artificial airways. Many life-threatening complications can occur when the procedure is not performed correctly. Although the evidence-based recommendations regarding ETS are available, many of these have not been observed in nurse’s clinical practice. We assessed the intensive care nurses’ knowledge and practice of ETS to intubated patients in selected hospitals in Dar es Salaam, Tanzania. Methodology A descriptive cross-sectional study design involving 103 Intensive Care Unit (ICU) nurses in Dar es Salaam city was conducted in 2014. Data were analyzed using SPSS version 20 where descriptive statistics were employed to interpret data. Results Majority of ICU nurses (69.9%) knew the indication for the procedure, (77.7%) knew the action to be taken in case of abrupt change in the ECG monitor; however, 80.6% demonstrated undesirable overall knowledge on ETS evidence-based recommendations. Nurses with ICU training (57.3%) significantly demonstrated higher knowledge of ETS than non-trained nurses (p

Jha, Ruchira M.; Elmer, Jonathan; Zusman, Benjamin E.; Desai, Shashvat; Puccio, Ava M.; Okonkwo, David O.; Park, Seo Young; Shutter, Lori A.; Wallisch, Jessica S.; Conley, Yvette P.; Kochanek, Patrick M.

Objectives: Intracranial pressure in traumatic brain injury is dynamic and influenced by factors like injury patterns, treatments, and genetics. Existing studies use time invariant summary intracranial pressure measures thus potentially losing critical information about temporal trends. We identified longitudinal intracranial pressure trajectories in severe traumatic brain injury and evaluated whether they predicted outcome. We further interrogated the model to explore whether ABCC8 polymorphisms (a known cerebraledema regulator) differed across trajectory groups. Design: Prospective observational cohort. Setting: Single-center academic medical center. Patients: Four-hundred four severe traumatic brain injury patients. Interventions: None. Measurements and Main Results: We used group-based trajectory modeling to identify hourly intracranial pressure trajectories in days 0–5 post traumatic brain injury incorporating risk factor adjustment (age, sex, Glasgow Coma Scale 6score, craniectomy, primary hemorrhage pattern). We compared 6-month outcomes (Glasgow Outcome Scale, Disability Rating Scale, mortality) and ABCC8 tag-single-nucleotide polymorphisms associated with cerebral edema (rs2237982, rs7105832) across groups. Regression models determined whether trajectory groups predicted outcome. A six trajectory group model best fit the data, identifying cohorts differing in initial intracranial pressure, evolution, and number/proportion of spikes greater than 20 mm Hg. There were pattern differences in age, hemorrhage type, and craniectomy rates. ABCC8 polymorphisms differed across groups. GOS (p = 0.006), Disability Rating Scale (p = 0.001), mortality (p < 0.0001), and rs2237982 (p = 0.035) differed across groups. Unfavorable outcomes were surprisingly predicted by both low intracranial pressure trajectories and sustained intracranial hypertension. Intracranial pressure variability differed across groups (p < 0.001) and may reflect preserved/impaired intracranial elastance/compliance. Conclusions: We employed a novel approach investigating longitudinal/dynamic intracranial pressure patterns in traumatic brain injury. In a risk adjusted model, six groups were identified and predicted outcomes. If validated, trajectory modeling may be a first step toward developing a new, granular approach for intracranial pressure phenotyping in conjunction with other phenotyping tools like biomarkers and neuroimaging. This may be particularly relevant in light of changing traumatic brain injury demographics toward the elderly. Drs. Zusman and Desai are joint third authors since they contributed equally to the final article. Dr. Jha was involved in study concept, design, data analysis, and interpretation and article generation. Dr. Elmer was involved in data and statistical analysis, group-based trajectory modeling and interpretation, and critical revision of the article. Drs. Zusman, Desai, Puccio, and Okonkwo were involved in acquisition of data and patient samples. Dr. Park was involved in statistical analysis and review. Drs. Shutter and Wallisch were involved in content expertise and critical revision of the article. Dr. Conley was involved in genetics content expertise, supervision, and critical review of the article. Drs. Kochanek was involved in study concept, design, data interpretation, supervision, and critical revision of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the following grants: The National Institutes of Health (NIH) (NINDS) K23NS101036 (to Dr. Jha), NIH (NINDS) 1K23NS097629 (to Dr. Elmer) NINR R01NR013342 (to Dr. Conley), NINR R00 NR013176 (to Dr. Puccio), NCATS KL2-TR000146 (to Dr. Jha), NCATS KL2-TR001856 (to Dr. Jha), UPP Foundation award (to Dr. Jha), University of Pittsburgh School of Medicine Dean’s Faculty Advancement Award (to Dr. Jha). Dr. Jha’s institution received funding from the National Institutes of Health (NIH) grants K23NS101036 (National Institute of Neurological Disorders and Stroke [NINDS]), KL2-TR001856 (National Center for Advancing Translational Science [NCATS]), KL2-TR000146 (NCATS). Drs. Jha, Elmer, Park, Wallisch, Conley, and Kochanek received support for article research from the NIH. Dr. Elmer’s institution received funding from NIH 1K23NS097629 (NINDS). Dr. Puccio received funding from NIH grant R00 NR013176 (National Institute of Nursing Research [NINR]). Dr. Conley’s institution received funding from NIH grant R01NR013342 (NINR). Dr. Kochanek’s institution received funding from the NIH and the Department of Defense, and he received funding from the Society of Critical Care Medicine/World Federation of Pediatric Intensive Critical Care Societies as Editor-in-Chief of Pediatric Critical Care Medicine, numerous lectures as a guest professor at a number of academic institutions, from serving as an expert witness on several cases relevant to pediatric neurocritical care, and as one of the editors of the Textbook of Critical Care Medicine (honorarium). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: jharm3@upmc.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Jeffrey C. Horowitz

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 4, Page 418-419, August 15, 2018.

Abstract Background Malaria continues to be a global burden as the efficacy of most commercial anti-malarial drugs has been compromised by the evolution of parasite resistance. With the urgent need created for the development of alternative and more efficient anti-malarial drugs, this study focused on the evaluation of anti-malarial agents of the Warburgia salutaris stem bark. Methods The stem bark was extracted with dichloromethane followed by silica gel column chromatography that led to the isolation of iso-mukaadial acetate, a drimanoid sesquiterpene. This compound was characterized by spectroscopic analysis (1H NMR, 13C NMR, IR and MS), and its structure was confirmed by X-ray crystallography. In vitro anti-plasmodial activity was investigated using a chloroquine sensitive NF54 Plasmodium falciparum strain. Cytotoxicity was measured using the MTT assay on HEK239 and HEPG2 cell lines. Chloroquine-sensitive Plasmodium berghei was used to infect Sprague–Dawley rats for in vivo studies. The W. salutaris crude extract and iso-mukaadial acetate were administered orally at 0.5; 1.5, 2.5 and 5 mg/kg, chloroquine was used as the reference drug. Determination of percentage parasitaemia, haematological parameters, and rat body weights was done throughout the experimental study period. Results The crude extract and iso-mukaadial acetate showed very good activity on the inhibition of parasite growth (IC50 0.01 ± 0.30 µg/ml) and (IC50 0.44 ± 0.10 µg/ml), respectively, with iso-mukaadial acetate having cytotoxicity activity of 36.7 ± 0.8 and 119.2 ± 8.8 (µg/ml) on HEK293 and HEPG2 cells, respectively. The crude extract and iso-mukaadial acetate reduced percentage parasitaemia in a dose-dependent manner in comparison to the control. There were no significant differences in the haematological parameters in all the experimental groups in comparison to control group. This study proves that W. salutaris contains components (including iso-mukaadial acetate) that exhibit anti-malarial activity. This study scientifically validates the use of this plant in folk medicine. Conclusions This study proves that Warburgia salutaris contains components (including iso-mukaadial acetate) that exhibit anti-malarial activity and scientifically validates the use of this plant in folk medicine.

Cyrille Lebon, Kevin Soupapoule, David A. Wilkinson, Gilbert Le Goff, David Damiens, Louis Clément Gouagna

by Cyrille Lebon, Kevin Soupapoule, David A. Wilkinson, Gilbert Le Goff, David Damiens, Louis Clément Gouagna The control of Aedes albopictus through Sterile Male Releases requires that the most competitive males be mass-reared and sterilized usually with gamma- or X-ray radiation prior to release. Developing an understanding of the impact of irradiation treatment on flight performance in sterile males is very important because any fitness cost may reduce the efficacy of SIT intervention in the field. Here, we examined the role of irradiation exposure and sugar-feeding on daily flight activity and performance of Ae. albopictus males sterilized during pupal stage with gamma-radiation at 35Gray from a Caesium 137 source. We used a previously developed automated video tracking system to monitor the flight activity of different groups of sterile and control non-sterile males over 24 hours in a flight arena. This monitoring took place under controlled laboratory conditions and we wished to quantify the daily flight activity and to highlight any changes due to radiation treatment and nutritional conditions (starved versus sugar fed). Our experimental evidence demonstrated a characteristic diurnal flight activity with a bimodal pattern regardless of the treatment. Precisely, both irradiated and non-irradiated males exhibited two distinct peaks in flight activity in the morning (6–8 a.m.) and late afternoon (4–6 p.m.). Under changing physiological conditions, irradiated males were generally more active over time and flew longer overall distances than control male populations. These results suggest some internal circadian control of the phase relation to the light-dark cycle, with evidence for modification of flight performance by nutritional status. The fact that daily activity patterns are alike in irradiated and control Ae. albopictus males, and that sterile males could display higher flight performance, is in contrast with the hypothesis that irradiation treatment appears to reduce the fitness of male mosquitoes. We discuss the implications of the present study in sterile-male release programs against Ae. albopictus.

Ho, K., Huo, W., Pas, S., Dao, R., Palmer, K. L.

Enterococcus faecalis is a Gram-positive opportunistic pathogen that inhabits the human gastrointestinal tract. Because of the high frequency of antibiotic resistance among Enterococcus clinical isolates, interest in using phage to treat enterococcal infections and to decolonize high-risk patients for antibiotic-resistant Enterococcus is rising. Bacteria can evolve phage resistance, but there is little published information on these mechanisms in E. faecalis. In this report, we identified genetic determinants of E. faecalis resistance to NPV1. We found that loss-of-function mutations in epaR confer NPV1 resistance by blocking phage adsorption. We attribute the inability of the phage to adsorb to the modification or loss of an extracellular polymer in strains with inactivated epaR. Phage-resistant epaR mutants exhibited increased daptomycin and osmotic stress susceptibilities. Our results demonstrate that in vitro spontaneous resistance to NPV1 comes at a cost in E. faecalis OG1RF.

Ali Ataya

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 4, Page P7-P8, August 15, 2018.

Abstract Background Vivax malaria reemerged along the Demilitarized Zone (DMZ), Republic of Korea (ROK), in 1993. While it was hypothesized that vivax malaria would spread throughout the peninsula, nearly all cases were due to exposure near the DMZ. To reduce spillover of vivax malaria to the civilian community, the ROK Ministry of National Defense (MND) initiated malaria prevention policies including a large-scale chemoprophylaxis programme in malaria high-risk areas in 1997. The present study investigated the overall changes in the incidence of malaria among ROK soldiers and the mass chemoprophylaxis program from 1997 to 2016. Results Peak numbers of vivax malaria were reported in 2000, with most cases reported near the DMZ, before declining to the current levels. To combat the rapid increase in the number of malaria cases and its expansion throughout the ROK, the MND implemented mosquito control and personal protection programmes. The MND also implemented a large-scale vivax malaria chemoprophylaxis programme using hydroxychloroquine (400 mg weekly) in 1997, and primaquine (15 mg × 14 days) as terminal chemoprophylaxis in 2001. Additionally, an improved medical system enabled the rapid detection and treatment of malaria to reduce morbidity and decrease transmission of malaria from humans to mosquitoes. Following the full implementation of these programmes, the incidence of vivax malaria declined in both ROK Armed Forces and civilian populations. Subsequently, several changes in the ROK Armed Forces chemoprophylaxis programme were implemented, including the reduction of the period of hydroxychloroquine prophylaxis by 2 months (2008) and other changes in the chemoprophylaxis policy, e.g., only ROK Armed Forces personnel in moderate risk groups received terminal primaquine chemoprophylaxis (2011), and in 2016, the discontinuation of terminal primaquine chemoprophylaxis in moderate-risk area. Conclusions The resurgence of vivax malaria in the ROK Armed Forces personnel near the DMZ was successfully suppressed through the implementation of a mass malaria chemoprophylaxis programme initiated by the MND in 1997, as well as several other factors that may have contributed to the reduction of malaria transmission since 2000. Given the current malaria situation in the ROK and North Korea, it is necessary to reevaluate the ROK Armed Forces and civilian malaria control policies.

Abstract Background Human granulocytic anaplasmosis is a tick-borne zoonotic disease caused by Anaplasma phagocytophilum, an obligate intracellular granulocytotropic bacterium. Case presentation A 70-year-old female patient was admitted with the clinical signs of fever and an altered state of consciousness 1 week after experiencing a tick bite while planting lawn grass. Magnetic resonance imaging, performed at the time of admission, indicated cerebral infarction in the left basal ganglia, whereas increasing immunofluorescence assay antibody titers for A. phagocytophilum were also documented. A. phagocytophilum was identified using groEL and ankA targeted polymerase chain reaction and sequencing. Because of severe thrombocytopenia, only doxycycline was administered, without any antiplatelet agents. Subsequently, the symptoms improved without any focal neurologic sequela. Conclusion This is the first reported case of cerebral infarction occurrence in an anaplasmosis patient.

Petryk, N., Dalby, M., Wenger, A., Stromme, C. B., Strandsby, A., Andersson, R., Groth, A.

During genome replication, parental histones are recycled to newly replicated DNA with their posttranslational modifications (PTMs). It remains unknown whether sister chromatids inherit modified histones evenly. Here, we measured histone PTM partition to sister chromatids in embryonic stem cells. We found that parental histones H3-H4 segregate to both daughter DNA strands with a weak leading strand bias, skewing partition at topologically associating domain (TAD) borders and enhancers proximal to replication initiation zones. Segregation of parental histones to the leading strand increased markedly in cells with histone-binding mutations in MCM2, part of the replicative helicase, exacerbating histone PTM sister chromatid asymmetry. This work reveals how histones are inherited to sister chromatids and identifies a mechanism for how symmetric cell division is ensured by the replication machinery.

Rees, V. E., Yadav, R., Rogers, K. E., Bulitta, J. B., Wirth, V., Oliver, A., Boyce, J. D., Peleg, A. Y., Nation, R. L., Landersdorfer, C. B.

Hypermutable Pseudomonas aeruginosa are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time-course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and non-hypermutable P. aeruginosa. Static concentration time-kill experiments over 72h assessed meropenem and ciprofloxacin in mono- and combination therapy against PAO1 (non-hypermutable), PAOmutS (hypermutable), and hypermutable isolates CW08, CW35 and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2g q8h as 3h infusion and 3g/day as continuous infusion) and ciprofloxacin (400mg q8h as 1h infusion) in monotherapies and combinations were further evaluated in an 8-day hollow fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48h. The maximum daily doses of 6g meropenem (T>MIC 80-88%) and 1.2g ciprofloxacin (AUC/MIC 176), both given intermittently, in monotherapy failed to supress regrowth and resulted in substantial emergence of resistance (≥7.6log10 CFU/mL resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable P. aeruginosa.

Abstract Purpose Pre-clinical animal studies precede the majority of clinical trials. While the clinical sepsis definitions and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking. To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling was held in Vienna in May, 2017. The conference goal was to identify limitations of pre-clinical sepsis models and to propose a set of guidelines, defined as the “Minimum Quality Threshold in Pre-Clinical Sepsis Studies” (MQTiPSS), to enhance translational value of these models. Methods 31 experts from 13 countries participated and were divided into 6 thematic Working Groups (WG): (1) Study Design, (2) Humane modeling, (3) Infection types, (4) Organ failure/dysfunction, (5) Fluid resuscitation and (6) Antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002–2013). Results Overall, the participants reached consensus on 29 points; 20 at “recommendation” (R) and 9 at “consideration” (C) strength. This Executive Summary provides a synopsis of the MQTiPSS consensus (Tables 1–3). Conclusions We believe that these recommendations and considerations will serve to bring a level of standardization to pre-clinical models of sepsis and ultimately improve translation of pre-clinical findings. These guideline points are proposed as “best practices” that should be implemented for animal sepsis models. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection and Intensive Care Medicine Experimental.

Ruth, M. M., Sangen, J. J. N., Pennings, L. J., Schildkraut, J. A., Hoefsloot, W., Magis-Escurra, C., Wertheim, H. F. L., van Ingen, J.

Mycobacterium abscessus (Mab) causes difficult-to-treat pulmonary disease (Mab-PD). After the initial intravenous treatment, minocycline is recommended in the oral continuation phase of treatment. We determined minimum inhibitory concentrations, synergy and time-kill kinetics of minocycline against Mab. With MICs of 8-512 mg/l, rapid emergence of tolerance in time-kill assays and no synergy with other drugs used to treat Mab-PD, minocycline appears ineffective against Mab. These in vitro data question its role as a Mab-PD treatment modality.

D. Ntirampeba, I. Neema, L. Kazembe

by D. Ntirampeba, I. Neema, L. Kazembe Background Making inferences about measles distribution patterns at small area level is vital for more focal targeted intervention. However, in statistical literature, the analysis of originally collected data on one resolution with the purpose to make inferences on a different level of spatial resolution is referred to as the misalignment problem. In Namibia the measles data were available in aggregated format at regional level for the period 2005 to 2014. This leads to a spatial misalignment problem if the purpose is to make decisions at constituency level. Moreover, although data on risk covariates of measles could be obtained at constituency level, they were not available each year between 2005 and 2014. Thus, assuming that covariates were constant through the study period would induce measurement errors which might have effects on the analysis results. This paper presents a spatio-temporal model through a multi-step approach in order to deal with misalignment and measurement error. Methods For the period 2005–2014, measles data from the Ministry of Health and Social Services (MoHSS) were analysed in two steps. First, a multi-step approach was applied to correct spatial misalignment in the data. Second, a classical measurement error model was fitted to account for measurement errors. The time effects were specified using a nonparametric formulation for the linear trend through first order random walk. An interaction between area and time was modelled through type I and type II interaction structures. Results The study showed that there was high variation in measles risk across constituencies and as well as over the study period (2005–2014). Furthermore, the risk of measles was found to be associated with (i) the number of people aged between 0 and 24 years, (ii) the percentages of women aged 15–49 with an educational level more than secondary, (iii) the percentages of children age 12–23 months who received measles vaccine, (iv) the percentages of malnourished children under 5 years, and (vi) the measles cases for each previous year. Conclusion The study showed some of the determinants of measles risk and revealed areas at high risk through disease mapping. Additionally, the study showed a non-linear temporal distribution of measles risk over the study period. Finally, it was shown that ignoring the measurement errors may yield misleading results. It was recommended that group and geographically targeted intervention, prevention and control strategies can be tailored on the basis these findings.

L. Tinoco-Gracia et al.

Abstract Purpose Mucormycosis (MCM) is a rare fungal infection affecting people with impaired immunity. Data related to MCM from Lebanon are scarce. The aim of this study is to shed light on the epidemiology, incidence, and outcome of patients with MCM hospitalized at a tertiary care center in Lebanon. Methods We conducted a retrospective chart review between Jan 1, 2008 and Jan 10, 2018. All patients with proven or probable MCM were included. Results A total of 20 patients were included. Their median age was 49 years and the majority were males. Comorbidities included mainly hematologic malignancy and diabetes mellitus. Most common sites of involvement were rhino-orbital and pulmonary, respectively. The number of MCM cases/10.000 hospital admissions increased significantly between 2008 and 2017 (0.47 vs. 1.18; P 

Michael D. Stutz, Marc Pellegrini

Mycobacterium tuberculosis interferes with the ability of its host cell to undergo apoptosis. Arnett et al. report that the pathogen promotes macrophage survival by engaging the nuclear receptor PPARγ to induce the antiapoptotic protein MCL-1, yielding insights into the pathogenesis of tuberculosis and potentially unlocking new avenues for therapeutic intervention.

In December 2017, the Boston radio station WBUR chronicled the case of the first patient at Massachusetts General Hospital to receive axicabtagene ciloleucel (Yescarta, Gilead) outside a clinical trial. The chimeric antigen receptor T cells (CAR-Ts) were made from 71-year-old Barbara Kearney’s own……

Kieran J. Rothnie

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 4, Page 464-471, August 15, 2018.

David Montani

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 4, Page 537-541, August 15, 2018.

Abbasi J.

A new nonprofit biotech organization funded by the Bill and Melinda Gates Foundation will take on infectious diseases that disproportionately affect the world’s poorest populations: malaria, tuberculosis, and enteric and diarrheal diseases in children. Together these diseases cause 5 deaths every minute, according to the new organization, the Bill and Melinda Gates Medical Research Institute.

Dang, W., Xu, L., Ma, B., Chen, S., Yin, Y., Chang, K.-O., Peppelenbosch, M. P., Pan, Q.

Norovirus is the main cause of viral gastroenteritis worldwide. Although norovirus gastroenteritis is self-limiting in immunocompetent individuals, chronic infections with debilitating and life-threatening complications occur in immunocompromised patients. Nitazoxanide (NTZ) has been empirically used in the clinic and demonstrated effectiveness against norovirus gastroenteritis. In this study we aimed at uncovering the antiviral potential and mechanisms of NTZ and its active metabolite, tizoxanide (TIZ) using a human norovirus (HuNV) replicon. NTZ and TIZ, collectively referred to as thiazolides (TZD) potently inhibited replication of HuNV and a norovirus surrogate feline calicivirus. Mechanistic studies revealed that TZD activated cellular antiviral response and stimulated the expression of a subset of interferon-stimulated genes (ISGs), particularly IRF-1 not only in Huh7-based HuNV replicon but also in naïve Huh7, Caco-2 and novel human intestinal organoids. Overexpression of exogenous IRF-1 inhibited HuNV replication; whereas knockdown of IRF-1 largely attenuated the antiviral activity of TZD, suggesting that IRF-1 mediated TZD inhibition of HuNV. By using a JAK inhibitor CP-690550 and STAT1 knockout approach, we found that TZD induced antiviral response independent of the classical Janus Kinase/signal transducers and activators of transcription (JAK/STAT) pathway. Furthermore, TZD and ribavirin synergized to inhibit HuNV replication and completely depleted the replicons from host cells after long-term treatment. In summary, our results demonstrated that TZD combated HuNV replication through activation of cellular antiviral response, in particular inducing a prominent antiviral effector IRF-1. NTZ monotherapy or combination with ribavirin represented promising options for treating norovirus gastroenteritis, especially in immunocompromised patients.

Shin, S. H., Jhun, B. W., Kim, S.-Y., Choe, J., Jeon, K., Huh, H. J., Ki, C.-S., Lee, N. Y., Shin, S. J., Daley, C. L., Koh, W.-J.

Mycobacterium avium complex (MAC) and M. abscessus complex (MABC) comprise the two most important human pathogen groups causing nontuberculous mycobacterial lung disease (NTM-LD). However, there are limited data regarding NTM-LD caused by mixed NTM infections. This study aimed to evaluate the clinical characteristics and treatment outcomes in patients with NTM-LD caused by mixed infection with these two major NTM pathogen groups. Seventy-one consecutive patients who had been diagnosed with NTM-LD caused by mixed infection with MAC (M. avium or M. intracellulare) and MABC (M. abscessus or M. massiliense) between January 2010 and December 2015 were identified. Nearly all patients (96%) had the nodular bronchiectatic form of NTM-LD. Mixed infection with MAC and M. massiliense (n = 47, 66%) was more common than mixed infection with MAC and M. abscessus (n = 24, 34%), and among the 43 (61%) patients who were treated for NTM-LD for more than 12 months, sputum culture conversion rates were significantly lower in patients infected with MAC and M. abscessus [25% (3/12)] compared with patients infected with MAC and M. massiliense [61% (19/31), P = 0.033]. Additionally, M. massiliense and M. abscessus showed marked differences in clarithromycin susceptibility (90% vs. 6%, P < 0.001). Of the 23 patients who successfully completed treatment, 11 (48%) redeveloped NTM lung disease, with mycobacterial genotyping results indicating that the majority of cases were due to reinfection. Precise identification of etiologic NTM organisms could help predict treatment outcomes in patients with NTM-LD due to mixed infections.

John E. McGinniss

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 4, Page 419-422, August 15, 2018.